Doutorado em Ciências Biológicas (ICB)

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Efeitos cardiovasculares da Hidroxicloroquina em animais normotensos e hipertensos
(Universidade Federal de Goiás, 2025-04-11) Costa, Jaqueline Moura da; Gomes, Rodrigo Mello; http://lattes.cnpq.br/3121095341590269; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Gomes, Rodrigo Mello; http://lattes.cnpq.br/3121095341590269; Macedo, Larissa Matuda; http://lattes.cnpq.br/5818563601876932; Rosa, Daniel Alves; http://lattes.cnpq.br/5848020104921718; Colugnati, Diego Basile; http://lattes.cnpq.br/3875833705952056
Hydroxychloroquine (HCQ) is widely used for the treatment of rheumatic diseases. Studies show that patients using this medication may experience cardiovascular and metabolic alterations. On the other hand, studies indicate that HCQ may have protective effects on the heart and metabolism. However, there are not many studies evaluating its effects under hypertensive conditions. Thus, the present study aimed to evaluate the cardiovascular effects of HCQ and whether these effects differ in hypertensive animals. Male normotensive (Wistar) and hypertensive (SHR, spontaneously hypertensive rats) rats, aged 16 weeks, were used. The experimental groups were divided into Wistar vehicle, Wistar HCQ, SHR vehicle, and SHR HCQ groups. The animals received either saline or HCQ (40 mg/kg/day) via gavage for 30 days. Body weight, water and food intake, systolic blood pressure (SBP), and heart rate (HR) were assessed weekly. SBP and HR were analyzed using tail-cuff plethysmography. Cardiac contractility was evaluated using the isolated heart technique under constant pressure. Aortic reactivity was assessed in isolated aortic rings using an organ bath system. The following organs were collected for weighing and/or histological and molecular analysis: left ventricle (LV), liver, pancreas, and white and brown adipose tissues. Normotensive animals treated with HCQ exhibited reduced body weight during the last two weeks of treatment compared to basal and the vehicle group at the same time. Both treated and untreated hypertensive animals showed a similar increase in body weight. The Wistar rats treated with HCQ consumed less feed and water than their control group, and there was a reduction in water intake in SHR. HCQ treatment did not significantly alter SBP in either strain; however, it increased HR in Wistar rats. Left ventricular function and coronary and aortic reactivity were not affected by HCQ. The ventricular mass index (VMI) was lower in Wistar HCQ rats, and cardiomyocyte diameter was reduced in both normotensive and hypertensive treated rats. HCQ did not alter the expression or phosphorylation of ERK1/2 or the activity of matrix metalloproteinase 2 in either strain. Superoxide dismutase (SOD) and catalase (CAT) expression was higher in Wistar HCQ animals but not in hypertensive ones. HCQ increased lipid peroxidation levels and the activity of SOD, CAT, and glutathione peroxidase in both Wistar and SHR rats. Treatment also reduced perivascular collagen in Wistar and interstitial collagen in SHR. HCQ reduced the immunohistochemical labeling for interleukin-1 beta (IL-1β) in the cardiac tissue of normotensive and hypertensive rats. HCQ reduced mesenteric, retroperitoneal, and epididymal fat mass in normotensive animals but not in hypertensive ones. Liver and pancreas weights were not affected by HCQ in either strain. Thus, it can be concluded that HCQ treatment affects the metabolic profile and cardiac morphology differently between normotensive and hypertensive animals. Notably, HCQ demonstrated better benefits in SHR, promoting greater protective effects against hypertrophy, cardiac fibrosis, and oxidative stress.
Efeitos do tratamento com Composto 21 durante a gestação de ratas hipertensas no sistema cardiovascular da prole
(Universidade Federal de Goiás, 2024-06-12) Bessa, Amanda de Sá Martins de; Fonseca, Silvia Carolina Guatimosim; http://lattes.cnpq.br/7958786029463633; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Fonseca, Silvia Carolina Guatimosim; http://lattes.cnpq.br/7958786029463633; Chaves, Maria Luiza de Morais Barreto de; http://lattes.cnpq.br/5968904641095466; Peixoto, Marco Fabrício Dias; http://lattes.cnpq.br/4660848298254835; Santos, Robson Augusto Souza dos; http://lattes.cnpq.br/3919711591553904
Hypertension is the main risk factor for developing other pathologies such as cardiac hypertrophy. Previous studies have shown that the AT2 receptor activation by Compound 21 (C21), an AT2 receptor agonist, promotes beneficial effects on the cardiovascular system. In addition, maternal exposure to beneficial factors proved important in mitigating or preventing the development of diseases in the offspring. Therefore, this study aimed to evaluate whether treatment with C21 during pregnancy in hypertensive rats could attenuate the development of hypertension and promote cardioprotective effects in the offspring. Spontaneously hypertensive rats (SHR) were treated with C21 (0.3 mg/kg/day, osmotic minipump) throughout the gestational period and females in the control group underwent the same surgical procedure but did not receive treatment. The systolic blood pressure was measured weekly by tail plethysmography between the 6th and 16th weeks of age. Cardiac function of the offspring was evaluated by echocardiography and the baroreflex and chemoreflex sensibility were assessed at 16 weeks old. Then, the animals were euthanized for evaluation of left ventricular function after ischemia and coronary reactivity by isolated heart preparation (Langendorff technique) and aortic vascular reactivity in the organ bath system. Samples of the left ventricle were collected for morphological and molecular analyses. Systolic blood pressure of the SHR C21 was lower than the control group from the 6th to the 16th week, without changes in heart rate. The experimental group showed greater baroreflex sensitivity (SHR -0.3530 ± 0.06 vs. SHR C21 -0.6594 ± 0.10 Δbpm/ΔmmHg, P<0.05). Echocardiographic parameters were not different between groups. The time of ischemia-reperfusion arrhythmia in isolated hearts was significantly reduced in the experimental group (SHR, 87.60 ± 34.13 vs. SHR C21, 5.66 ± 4.91 seconds, P<0.05). Coronary vasodilation in response to bradykinin was improved in the treated group (SHR, -2.87 ± 1.25 vs. SHR C21, -12.96 ± 3.28 %, P<0.05). However, aortic vascular reactivity was not different between groups. Maternal treatment with C21 reduced cardiomyocyte area (SHR, 396.9 ± 6.33 vs. SHR C21, 320.5 ± 6.44 μm2, P<0.05), and interstitial (SHR, 15.93 ± 0.85 vs. SHR C21, 8.92 ± 0.49 %, P<0.05) and perivascular fibrosis (SHR, 1.93 ± 0.14 vs. SHR C21, 1.18 ± 0.13 μm2, P <0.05) in left ventricles of offspring. Nuclear factor of activated T-cells (NFAT) total (SHR, 41,65 ± 3,49 vs. SHR C21, 27,01 ± 2,72 a.u., P<0,05) and nuclear (SHR, 3,09 ± 0,23 vs. SHR C21, 1,01 ± 0,13 a.u., P<0,05) expression was lower in the treated group. The expression of proteins involved in pathways related to pathological cardiac remodeling was not different between the groups. The expression of AT1 and AT2 receptor proteins in the heart was also not altered by maternal treatment. These results demonstrate that maternal treatment of spontaneously hypertensive rats during pregnancy with C21 can attenuate the development of hypertension and promote cardioprotective effects in the offspring. These data suggest that AT2 receptor activation during pregnancy may be a potential therapeutic strategy for the prevention of cardiovascular disorders in offspring.
Efeitos da exposição controlada a agentes estressores sobre os marcadores bioquímicos de militares do Exército Brasileiro durante curso de alta intensidade
(Universidade Federal de Goiás, 2024-12-19) Vieira, Stéfani Kárita Lima da Silva; Pinheiro, Denise da Silva; http://lattes.cnpq.br/1306832039941065; Pedrino, Gustavo Rodrigues; lattes.cnpq.br/1155446449250341; Pedrino, Gustavo Rodrigues; lattes.cnpq.br/1155446449250341; Pinheiro, Denise da Silva; http://lattes.cnpq.br/1306832039941065; Barros Neto, Turíbio Leite de; http://lattes.cnpq.br/7124570885980929; Oliveira, André Henrique Freiria de; http://lattes.cnpq.br/0152151142555605; Rosa, Daniel Alves; http://lattes.cnpq.br/5848020104921718
The Activity of Controlled Exposure to Stressors (AECAE), associated with physiological wear promoted by the continued training of troops of the Brazilian Army (EB), may contribute to the development of rhabdomyolysis by strenuous exercise or effort rhabdomyolysis (ER). Characterized by the rupture of the membrane of skeletal muscle cells, ER leads to increased serum levels of intracellular proteins and renal overload, with symptoms that include muscle fatigue, weakness and brown urine. These symptoms can be obscured by exhaustion of training, resulting in irreparable kidney damage or even death. The present study aimed to evaluate the effects of AECAE on serum biochemical markers and the incidence of ER, in order to identify biochemical predictors that may indicate susceptibility to the development of ER among subjects submitted to AECAE. We also sought to evaluate the AECAE impact on the physical and biochemical health of individuals, by measuring various serum biomarkers at different times in AECAE. Of these, 49 soldiers were submitted to AECAE (case group) and 61 soldiers were not submitted to AECAE (control group). All protocols were approved by the UFG’s Research Ethics Committee (Opinion No. 6.287.272/UFG). Serum levels of 23 biochemical markers were measured during four moments evaluated in the study: basal (7 days before the beginning of AECAE; C1); minimum AECAE (exposure onset; C2); maximum AECAE (peak exposure; C3) and recovery (48 hours after the end of AECAE Maximum; C4). AECAE was designed to train participants under situations of physical, psychological, water and nutritional stress in a controlled manner. The protocol sought to simulate extreme conditions within a monitored environment to ensure the safety of those involved and the integrity of the data collected. All laboratory information was made available through an anonymized database. To determine the liver and kidney function, the ratios between AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and between urea and creatinine were calculated, respectively. The serum creatine phosphokinase (CK) concentration > 1000U/L was used as a criterion for defining ER. During the peak AECAE, increased serum levels of CK, Lactic Dehydrogenase (LDH), AST, alanine aminotransferase (ALT), Creatine Phosphokinase Miocárdica (CK-MB), uric acid, total and direct bilirubin, creatinine, urea, urea/creatinine ratio, high density lipoprotein (HDL), phosphorus (P+), magnesium (Mg+) and total calcium (Ca2+). These values were also significantly higher than those observed in the control group. In addition, 48 hours after the end of maximum exposure, it was observed that the levels of LDH, CK, CK-MB, AST, ALT and Urea/Creatinine ratio were still elevated in subjects submitted to AECAE. In addition, based on the increase of the muscle degradation marker (CK>1000), it was found that 6% of the individuals in the group developed risk of ER in the minimum AECAE and 51% in the maximum AECAE. In relation to the risk predictors, we identified that individuals from the experimental group with basal values of urea/creatinine 28 ratio have 3.6 times more chances of developing ER during high intensity exercise (OR = 3.64 [1.11-11.97]; p = 0.03). The analysis of possible biochemical markers to determine susceptibility to success or failure in stressful situations, showed that individuals with higher baseline concentrations of direct bilirubin and CK and lower plasma levels of urea, CK-MB and LDH have a greater predisposition to success before exposure to high intensity physical and psychological stressors. The results of this study demonstrate that AECAE causes significant changes in several serum biochemical markers, which are indicative of muscle stress and organ dysfunction. Notably, even 48 hours after the end of AECAE, many of these markers have not yet returned to their baseline values, suggesting that this period may not be adequate to ensure complete muscle and renal recovery. In addition, the basal level of urea/creatinine ratio 28 has the potential to be used as a predictor of susceptibility to ER development during AECAE, allowing the selection of subjects and risk mitigation of developing this condition, that should be better investigated in future studies. Finally, the basal biochemical profile of direct bilirubin, CK, urea, CK-MB and LDH can serve as a promising indicator of greater resilience and success in high intensity stressful situations.
Mecanismos envolvidos na atividade gastroprotetora do extrato hexânico das folhas de Celtis iguanaea (JACQ.) Sargent (Cannabaceae) e da fração aquosa do extrato hidroacetônico de Eugenia uniflora L. (Myrtaceae)
(Universidade Federal de Goiás, 2015-05-29) Martins, José Luís Rodrigues; Costa, Elson Alves; Costa, Elson Alves; Malvar, David do Carmo; Ferreira, Anderson Luiz; Paula, Joelma Abadia Marciano de; Menegatti, Ricardo
Peptic ulcer disease is a major cause of morbidity and mortality, and is characterized by deep lesions in the gastric mucosa. The pathophysiological of peptic ulcer is described as an imbalance between aggressive factors such as hydrochloric acid, pepsin and protective factors of gastric mucosa, such as mucus, bicarbonate, nitric oxide (NO), prostaglandins and blood flow. In Brazil, ethnopharmacological studies report the use of Celtis iguanaea (Jacq.) Sargent and Eugenia uniflora L. for the treatment of gastrointestinal disorders. The objective of this study was to investigate the possible mechanisms involved in the gastroprotective activity of extract hexane of leaves Celtis iguanaea (Jacq.) Sargent (EHEG), of the aqueous fraction of hydroacetonic extract from the leaves of Eugenia uniflora (FAHP) and phytoconstituentisolated from FAHP (Oenothein B). Male albino Swiss mice adult weighing between 35-40 g or male albino Wistar rats adult weighing between 180-200 g. Were used in this study the EHEG produced antiulcer activity in different in vivo models, such as stress, HCl/EtOH and acetic acid induced ulcer. The EHEG at dose of 100 mg/kg administered orally (p.o.) or intraduodenally (i.d.) increased the binding capacity of the Alcian blue adhered to the gastric mucus. In model to evaluate the role of α2-adrenoceptor was observed that pretreatment with yohimbine (an antagonist α2-adrenergic) reduced gastroprotection produced by EHEG (100 mg/kg, p.o.). In model to assess the role of NO was observed that pretreatment with L-NAME (NG-L-Nitroarginine methyl ester - non-specific NOS inhibitor) reduced gastroprotection exercised by EHEG (100 mg/kg, p.o.) and in model to evaluate the role of prostaglandins (PGs) endogenous, was observed that pretreatment with indomethacin (an inhibitor of cyclooxygenase enzyme) reduced the astroprotection effect of EHEG (100 mg/kg, p.o.). This study also showed that animals treated with FAHP in doses of 10, 30, 100, 300 and 1000 mg/kg or vehicle (distilled water) prduced not activity, when compared with the control group in overral pharmacological activity test. FAHP has antiulcer activity in different models of induced ulcers in vivo, such as indomethacin, stress and HCl/EtOH. FAHP in the dose of 300 mg/kg given orally increased binding capacity Alcian blue adhered to the gastric mucosa and the levels of GSH. In assessing the antissecretory activity, FAHP (300 mg/kg, i.d.) was able to reduce the free acidity (pH) and total acidity. In model to evaluate the role of NO was observed that retreatment with L-NAME did not reduce the gastroprotection exerted by FAHP. The oenoteína B also showed antiulcerogenic activity in different models of induced ulcers in ivo, such as indomethacin, HCl/EtOH and pyloric ligation. In an attempt to elucidate the possible mechanisms of action were performed ex vivo bioassays. The oenothein B (15 mg/kg,p.o.) was able to increase the activity of catalase (CAT) in the gastric mucosa. In model to evaluate the role of prostaglandins (PGs) Endogenous was observed that retreatment with indomethacin, reduced gastroprotection produced by oenothein B. However, the treatment with oenothein B did not prevented the reduction of the levels of PGE2 in the gastric mucusof rats pretreated with indomethacin. In the study of antissecretory activity, treatment with oenothein B (15 mg/kg i.d.) was able to reduce the amount of gastric acid secretion (mL) and total acidity. The findings of this study suggest that EHEG, FAHP and oenothein B have gastroprotective activity against the several ulcerogenic agents used. The gastroprotection was related mainly to the increase of protective factors (NO, PGs, mucus or antioxidant activity), but also there was a reduction of aggressive factors (gastric acid secretion).
Estudo do potencial citotóxico e do mecanismo de morte celular de novos protótipos à base de rutênio frente a diferentes células tumorais
(Universidade Federal de Goiás, 2014) Lima, Aliny Pereira; Lacerda, Elisângela de Paula Silveira; Lacerda, Elisângela de Paula Silveira; Bérgamo, Nádia Aparecida; Ayres, Flávio Monteiro; Cortez, Alane Pereira; Santos, Wagner Gouvêa dos
Currently ruthenium complexes have demonstrated interesting anticancer properties and may represent new and effective therapeutic agents for use as drugs alternative to platinum drugs. The present study aimed to investigate in vitro the cytotoxic and pro-apoptotic effect of the ruthenium complex cis-(dichloro)tetrammineruthenium(III) chloride against human lung alveolar carcinoma (A549) and complexes of ruthenium (II) coordinated to different amino acids against Sarcoma 180 tumor cells through the techniques of cell viability assay, kinetics of cell cycle phases assay, annexin V/propidium iodide assay, mitochondrial membrane potential assay, gene expression by real time PCR assay and western blotting assay. The cell viability assay by MTT reduction technique, it was found that complexes of ruthenium (II) coordinated to amino acids showed cytotoxic activity against S180 tumor cells with IC50 values ranging from 22.53 to 70.08 µM. For ruthenium complex (III) cis- (dichloro)tetrammineruthenium(III) chloride the IC50 value against A549 tumor cells was greater than 383 µM (IC50> 383 mM). Additionally, it was observed that complexes of ruthenium (II) exhibited low cytotoxicity on normal cells of mouse fibroblast L929, with IC50 values ranging from 27.39 to 106.72 µM. The clonogenic assay was performed in A549 tumor cells, and by the results obtained it was found that at low concentrations of the complex cis-(dichloro)tetrammineruthenium(III) chloride (0.38 and 3.8 µM) there was a decrease in the ability of cells to form colonies and at high concentrations 95 and 383 µM there was no colonies formation In cell cycle analysis of S180 tumor cells treated with complex of ruthenium (II) RuGly the results showed that this complex increased the percentage of cells in G0/G1, which correlated with consequent reduction in the number of cells in S phase. To complex of ruthenium (III) cis-(dichloro)tetrammineruthenium(III) chloride against A549 tumor cells, it was found that this complex increased the percentage of cells in S phase. In the analysis of apoptosis assays, the results showed that the complex ruthenium (II) RuGly induced cell death via apoptosis in S180 tumor cells as evidenced by the increase in annexin V positive cells, depolarization of the mitochondrial membrane potential, activation of caspase 3, 8 and 9 and increased expression levels of Caspase-3 (mRNA) and Bax (mRNA) and Bak (protein). The expression of genes Caspase-8, Caspase-9 and Tp53 remained unchanged during the period of exposure examined. For complex ruthenium (III) induction of apoptosis on A549 cells was verified by the presence of annexin V positive cells and peak in sub-G1 (indicative of apoptosis) and increased levels of mRNA of Caspase 3. In addition cell death via necrosis was observed as verified by increased number of cells labeling with only propidium iodide. From the results it is concluded that both complexes of ruthenium (II) and (III) to induce cytotoxic activity against cell models tested and this activity correlates with alterations in cell cycle phases and induction of cell death via apoptosis and necrosis, being prototypes promising drugs against tumor models investigated.
Morfo-anatomia, variabilidade química e atividade biológica do óleo fixo de sementes de apeiba tibourbou aubl. – malvaceae
(Universidade Federal de Goiás, 2010-12-15) Barros, Marilda da Conceição Ribeiro e; Paula, José Realino de; Paula, José Realino de; Silva, Heloísa Torres da; Ferreira, Heleno Dias; Magalhães, Roberto Toledo de; Leandro, Wilson Mozena
Apeiba tibourbou Aubl. is a arboreal plant found in Central America, northern Brazil to Minas Gerais and São Paulo. Is well distributed in the Central West region of Brazil. The oil from its seeds is used in Costa Rica to reduce hair loss and spasms treatments. This study aimed to perform a morpho-anatomic and histochemical leaves, flowers and fruit of Apeiba tibourbou and evaluate the physicochemical properties, lipid profile and power analgesic and anti inflammatory effect of the fixed oil from seeds by paw edema, formalin and carrageenan methods. Samples of leaves, bark, flowers and fruits were collected from five individuals (specimens). Samples were collected in the cities of Goiânia, Itauçu and Mossâmedes (Serra Dourada Environmental Reserve). Morphoanatomy leaves, flowers and fruits was performed by standard techniques. The fruits were manually benefited and the oil extracted was analyzed as to their physical-chemical properties and lipid profile. Samples of soil and leaves were collected and analyzed for the level of macro and micronutrients. Morphoanatomy showed anatomic patterns matching those already presented by other authors for Malvaceae. The following structures were observed: glandular and stellate trichomes were distributed by all organs of the plant. Secretory cavities present in almost all cross-sections performed. The average yield of the fixed oil of the seeds was 23.83%. The major constituent was 25.42% with lauric acid, found in all samples. Palmitic with 23.50% was the second major, linoleic acid, in third place with 11.51%. The fourth in per cent, with oleic acid and 9.30% in the fifth with -linolenic acid 8.11%. With 3.27% eicosapentaenoic acid (EPA) should also be considered the presence of docosahexaenoic acid (DHA) at 0.78%. In multivariate analysis of the organic-chemical and environmental data of leaves, soil and seed oil was observed that there is no change to oil chemistry regarding the environmental data. Regarding the analysis of biological activity of fixed oil of A. tibourbou, showed the same power and anti inflammatory analgesic method of writhing induced by acetic acid method of pain induced by formalin and paw edema induced by carrageenin. In this study, we observed that the oil of A. tibourbou presents as main constituent fatty acid omega 3, omega 6, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), lauric acid and palmitic acid. Can be used with food and medicinal purposes.
Morfologia, Farmacologia e Fitoquímica foliar de Erythroxylum campestre A. St. -Hil. e Erythroxylum. deciduum A. St. -Hil. (Erythroxylaceae)
(Universidade Federal de Goiás, 2011) Safadi, Giuliana Muniz Vila Verde; Paula, José Realino de
The genus Erythroxylum belonges to the family Erythroxylaceae, wich is presented by four genera and 130 species occurring in tropical and subtropical the world. How has the best known, Erythroxylum coca Lam. is an important source of tropane alkaloids such as cocaine. Thus, this paper describes in article form, the morphological, pharmacological and phytochemical studies of the leaf from two Cerrado’s species, as the Erythroxylum campestre A. St. Hil. and Erythroxylum deciduum A. St. Hil. The article 1 deals with both morphoanatomical species, which can perfectly be used as parameters of differentiation between them. In cross section the characteristics that vary more between species were: outline of the main vein, so the system vascular in midrib and petiole; cuticle with or without ornamentations; epicuticular wax; shaped crystals of druse, which may occur in the epidermis, the pith of the main vein and between veins of smaller caliber, ratios of intercellular spaces in parenchyma. Papillary cells were observed, sclereids in E. campestre. In histochemical analysis, lipophilic compounds, compounds phenolics, starch in virtually all tissues of the leaf blade. In article 2, we determined the standards for purity and integrity a drug of the two species as well as the profiles were determined chemicals. It was observed the presence of flavonoids, tannins and resins in E. campestre, and triperpenos, alkaloids, flavonoids and tannins in E. deciduum. Article 3 deals with the General and specific pharmacological evaluation of crude ethanol extract of species, used in doses of 100, 300 and 1000 mg / kg. In test pharmacological activity generally observed behaviors challenging, followed by depression for E. deciduum, being on the rota rod test and time activity test of barbiturate-induced sleep, both extracts no significant effect. In the open field, there was motor impairment caused by E. deciduum extract, inhibiting the locomotion animals in 37% and no meaningful action to E. campestre extract. Yet the production of fecal material from animals treated with E. country was significantly increased from 3.0 ± 6.0 and E. deciduum decreased 3.5 ± 0.5.These studies suggest further research on the action laxative E. campestre and motor impairment of E. deciduum. In article 4, the evaluation of essential oils identified 34 compounds for both species, and these are phenylpropanoids 4.76%, 38.09% of sesquiterpenes, 33.33% of monoterpenes. Of these, only 4 are common between both species. Although, we evaluated the composition of the soil, where species were collected, because it is known that there is an impact on production secondary metabolites. The soil has dystrophic character (V ≤ 50%) and moderately acid (pH = 5.3), low cationic exchange capacity, and calcium and manganese and potassium ions as the predominant complex exchanges soil. This paper is an initial contribution to the studies of a genus whose species are found in a wide diversity in Cerrado of Goiás and it deserves attention.
Estudo da atividade vasorrelaxante da fração butanólica das folhas de caryocar brasiliense camb. e do ácido gálico em aorta torácica de ratos
(Universidade Federal de Goiás, 2015) Oliveira, Lais Moraes de; Filgueira, Fernando Paranaíba; Ghedini, Paulo César
Caryocar brasiliense Camb., known as pequi, is a typical Brazilian Cerrado tree. Previous study showed that butanolic fraction (BF) of pequi leaves presents endothelium dependent vasorelaxant effect in rat aortic preparations by stimulation of the nitric oxide/guanylyl cyclase (NO/sGC) pathway. In addition, the preliminar chemistry characterization of BF showed the presence of the quercetin and gallic acid phenolic compounds. Considering these informations, the presente study was performed with the aim to identify the mechanisms involved in the activation of NO/sGC pathway by BF and to those involved in the vasorelaxant effect of gallic acid (GA), that it is a compound of BF. The action mechanisms were evaluated on the BF and GA vascular reactivity in the presence of protein agonists and antagonists in isolated preparations of rat thoracic aorta rings. The results of the vascular reactivity were confirmed with the Western blotting technique. In addition, the chemistry characterization of BF was determined with the high-resolution mass spectrometry. The BF promoted vasorelaxant effect in rat thoracic aorta rings in a concentration- dependent manner in preparations with vascular endothelium, which was decreased in the presence of Ca2+/CaM complex inhibitor (calmidazolium) and Pl3-kinase inhibitor (wortmannin). However, the incubation of aortic preparations with KN-93 (Ca2+/CaM dependent protein kinase II inhibitor) and PP2 (Src kinase inhibitor) did not inhibit the vasorelaxation induced by BF. Western blotting tests confirmed that BF caused phosphorylation of eNOS in the Ser1177 residue, effect mediated by the Pl3- kinase/Akt pathway. The chemistry characterization of BF identified the presence of 72 compounds, and the most of them are phenolic compounds and its derivatives. The GA promoted vasorelaxant effect in a concentration-dependent manner in the higher concentrations (0.4-10 mM). The aortic relaxation induced by GA was not abolished by removal of the vascular endothelium. The incubation with the nitric oxide synthase inhibitor (L-NAME), a guanylate cyclase inhibitor (ODQ), or the Ca2+/CaM complex inhibitor (calmidazolium), non-specific potassium channel blocker (TEA), or the blocker voltage-dependent potassium channel (4-aminopyridine) and with the potassium channel blocker type rectifiers (barium chloride) significantly reduced the GA pEC50 values. In addition, GA caused phosphorylation of eNOS in the Ser1177 residue. The results showed that prostanoids vasodilators, Pl3-kinase, Src-Kinase and calcium dependent and sensitive ATP potassium channels are not involved in the vasorelaxant effect promoted by the GA. The incubation with GA promoted reduction of CaCl2-induced contractions and blocked BAY K8644-induced vascular contractions, but it did not inhibit the contraction induced by the release of Ca2+ from the sarcoplasmatic reticulum stores. The results here obtained showed that vasorelaxant effect promoted by FB in aortic rats is due to the phosphorylation of eNOS by Pl3-kinase/Akt pathway and that this effect is caused by the phenolic compounds of BF. On the other hand, the vasorelaxant effect of GA involves endothelium-dependent and -independent mechanisms, as the phosphorylation of eNOS at Ser1177 position and the inhibition of the calcium influx via L-type Ca2+ channels. Taken together, these results help us to understand the action mechanisms involved in the endothelium dependent vasorelaxant effect of BF and for to elucidate the possible compounds associated with this effect. In another way, this study contributes for a better knowledge of the action mechanisms associated with the GA vasorelaxant effect.
Fitoquímica, morfoanatomia e atividade antimicrobiana de Lippia sidoides Cham., Lippia lupulina Cham. e Lippia pohliana Schauer (Verbenaceae) e atividade farmacológica de L. sidoides originária de Minas Gerais
(Universidade Federal de Goiás, 2014-03-21) Morais, Sandra Ribeiro de; Rezende, Maria Helena; Paula, José Realino de; Paula, José Realino de; Almeida, Jackson Roberto Guedes da Silva; Nunes, Xirley Pereira; Fiuza, Tatiana de Souza; Tresvenzol, Leonice Manrique Faustino
Verbenaceae family has been widely studied due to the presence of aromatic principles founded in many species used in folk medicine. The aim of this work is to perform the morphoanatomic description, phytochemical study and biological activity of leaves of Lippia sidoides originating from Fortaleza, Ceará and São Gonçalo do Abaeté, Minas Gerais, and leaves of Lippia lupulina and Lippia pohliana originating Mossâmedes, Goiás. For all species, anatomic analyses were performed microtechniques photonic and electronic scanning; essential oil was obtained by hidrodestilation, chemically characterized by GC/MS; the broth microdilution method was used to evaluate the antimicrobial activity of the essential oil, the crude ethanol extract and the hexanic, dichloromethane, ethyl-acetate, and aqueous fractions. Crude ethanol extract of L. sidoides originating from Minas Gerais, was tested in mice for to evaluate the antinociceptive, anti-inflammatory, and central nervous system activities. Anatomical features common to Verbenaceae were observed in the species studied, as amphistomatic leaves with glandular and tector trichomes, dorsiventral mesophyll and vascular system in the midrib in open arc; differences in the anatomy of the leaf surface of two accessions of L. sidoides were observed. The occurrence of chemotypes in L. sidoides was confirmed by analysis of the chemical composition of essential oil of two accesses. The crude ethanol extract and the dicloromethane and hexanic fractions of L. sidoides originating from Minas Gerais had the best profile for antimicrobial activity in vitro against Candida and Cryptococcus. Essential oil of L. lupulina had antimicrobial activity against Bacillus Subtilis, Micrococcus roseus, Micrococcus luteus, Staphylococcus aureus and Cryptococcus sp. It was registered moderated activity to essential oil of L. pohliana against S. aureus; of the crude ethanol extract and hexanic fraction against Bacillus cereus and Staphylococcus aureus; of the hexanic fraction against Enterobacter aerogenes, Enterobacter cloacae, Cryptococcus gatti e Cryptococcus neoformans, and of the dichloromethane fraction against Cryptococcus gatti. The crude ethanol extract had antinociceptive and anti-inflammatory activities in mice.
Caracterização preliminar de genes myb no genoma de eucalyptus spp
(Universidade Federal de Goiás, 2011) Bandeira, Ludmila Ferreira; Coelho, Alexandre Siqueira Guedes
Transcription factors are important regulators of gene expression that contains a binding domain that recognizes DNA in a specific manner and regulate the frequency of initiation of transcription by binding to promoters of target genes. Based on the similarity of the DNA binding domain, these proteins are grouped into different families. In plants, the MYB family of transcription factors is one of the largest and its members have been linked to different biological and biochemical processes, such as the control of cell morphogenesis, including the development of trichomes, roots and petals. Members of this family of transcription factors also act in the control of metabolism, particularly in regulating the synthesis of phenylpropanoids such as flavonoids, anthocyanins and lignins. Some members are also involved in regulating the response to phytohormones, including abscisic acid and gibberlins and also in response to environmental signals like light and availability of water. Some members of the R2R3-MYB subfamily has the ability to bind to AC elements that are commonly present in the promoters of genes participating in lignin biosynthesis, regulating specific steps of the biosynthesis of these molecules. As part of the data mining efforts of the vast amount of information available from Eucalyptus genome projects, this work performed the preliminary identification and annotation of transcription factors of the MYB family in the genome of Eucalyptus species in a attempt to identify those genes whose products are linked to lignin synthesis. Orthologous relationships between myb genes of Eucalyptus and those of other species described in the literature were inferred using phylogenetic analyses tools, allowing the identification of its putative functions. The evaluation of the expression profiles of 21,442 unigenes developed under the Genolyptus project allowed the investigation of the expression patterns of myb genes in two Eucalyptus species (E. grandis and E. globulus) and plant tissues (leaf and xylem). We also tried to integrate the information provided by published genetic maps of microsatellite markers containing QTLs for lignification with data from the Eucalyptus genome sequencing project. Co-localization of myb genes with QTLs for these characters has allowed the identification of myb genes of interest for future studies in functional genomics. We identified 212 genes belonging to the MYB family of transcription factors in the genome of different species of Eucalyptus. Each of these genes was submitted a process of manual annotation, and 177 of these were classified as myb-R2R3, and characterized in terms of its ultra-structure of introns and exons. The analysis of the results obtained by the use of three different methodologies: molecular phylogeny, analyses of expression and co-localization with QTLs, allowed the identification of candidate genes that are likely involved in the control of lignin content and quality in Eucalyptus. EucMYB_024, EucMYB_032, EucMYB_044, EucMYB_046, EucMYB_050 and EucMYB_068 showed evidence under the three methodologies that suggest they are involved in an important way in the process of xylogenesis in Eucalyptus. The results herein are useful in allowing the identification of target genes for future studies in functional genomics. Apparent functions were associated with these six genes. The understanding of their role in the development of Eucalyptus wood will be effectively established in future studies of genetic transformation, where the effects of overexpression and silencing of these genes may be assessed.
Efeito neuroprotetor da inibição do transportador de prolina (SLC6A7)
(Universidade Federal de Goiás, 2024-11-29) Carvalho, Gustavo Almeida de; Oliveira, Antônio Carlos Pinheiro de; http://lattes.cnpq.br/2124700239916112; Pinto, Mauro Cunha Xavier; http://lattes.cnpq.br/0868250984727943; Pinto, Mauro Cunha Xavier; Torres, Bruno Benetti Giunta; Pedrazzi, João Francisco Cordeiro; Lima, Onésia Cristina de Oliveira; Colugnati, Diego Basile
This study investigates the role of L-proline and the proline transporter (PROT, Slc6a7) in modulating glutamatergic neurotransmission and explores potential therapeutic approaches for neurodegenerative diseases. We demonstrated that L-proline influences intracellular calcium content in cortical and hippocampal synaptosomes of mice, observing an increase in intracellular calcium content at higher doses. We also assessed the impact of L-proline on motor and exploratory behavior in mice using the open field test. High concentrations of L-proline were found to reduce animal mobility without inducing anxious behaviors. In contrast, lower concentrations showed a stimulatory, though not significant, effect, suggesting a dual concentration-dependent effect of L-proline. We performed gene and protein expression analyses to elucidate the distribution and function of PROT in the brain. Our findings revealed that PROT is highly expressed in the cortex, striatum, and hippocampus, indicating possible regional specialization of its function. Furthermore, we investigated the interaction of PROT with potential inhibitors, such as iPROT, LQFM215, and LX6171, through modeling and molecular docking. These analyses revealed that both inhibitors bind effectively to PROT, with implications for modulating glutamatergic neurotransmission. Analyzing the effects of the proline transporter inhibitor (iPROT) in synaptosomes, we observed that iPROT mimics the effects of L-proline, increasing intracellular calcium content. We also explored the behavioral impact of iPROT, noting reductions in motor and exploratory behavior in mice without inducing anxiety-like behavior. Finally, we evaluated the neuroprotective potential of iPROT in an animal model of neurodegeneration induced by intrahippocampal Aβ injection. Pretreatment with iPROT demonstrated memory preservation and prevention of dendritic spine loss, indicating significant therapeutic potential. The analysis of key proteins involved in glutamatergic neurotransmission and the Brain-Derived Neurotrophic Factor (BDNF) pathway suggests a neuroprotection mechanism associated with these pathways. This study provides valuable insights into the neurobiology of L-proline and PROT, paving the way for new therapeutic approaches in neurodegeneration.
Potencial bioativo de nanopartículas de peju acetilado contendo óleo essencial de citrus sinensis: avaliações in vitro e in vivo
(Universidade Federal de Goiás, 2024-09-27) Silva, Cassio Nazareno Silva da; Leal, Maria Carolina Bezerra Di Medeiros; http://lattes.cnpq.br/4218546260742052; Batista, Karla de Aleluia; http://lattes.cnpq.br/9859814532588957; Batista, Karla de Aleluia; Santos, Fernanda Cristina Alcantara dos; Pedrino, Gustavo Rodrigues; Marreto, Ricardo Neves; Cruz, Maurício Vicente
The essential oil of Citrus sinensis is a terpenoid mixture mainly composed of d-limonene and exhibits several biological activities described in the literature, including anti-inflammatory, antioxidant, antibacterial, and antiarrhythmic properties. However, it is still underutilized as a therapeutic compound by the pharmaceutical industry due to its limitations, such as low water solubility, susceptibility to oxidative processes, and poor absorption in the gastrointestinal tract. An alternative to mitigate these issues is the encapsulation of C. sinensis essential oil in polymeric nanoparticles, as they have the potential to improve the bioavailability of the active ingredient, protect the molecule from degradation in the gastrointestinal tract, and allow controlled release, reducing its degradation and clearance in biological systems. Thus, the present study aimed to nanoencapsulate C. sinensis essential oil (EO) using acetylated polysaccharides extracted from cashew gum as the polymeric matrix (acCGP@EO) and to evaluate the biological potential of the produced nanosystem. The nanoparticles were produced by nanoprecipitation and evaluated regarding their encapsulation efficiency, hydrodynamic diameter, polydispersity index, zeta potential, and morphology using transmission electron microscopy. Considering the purpose of testing the acCGP@EO in animal models, we first evaluate the cellular toxicity through the MTT assay. Results evidenced that the EO and acCGP@EO did not show baseline cytotoxicity at the tested concentrations, evidencing the safety of the non-nanostructured EO and the produced acCGP@EO nanoparticles. Also, the acCGP@EO nanoparticles protected cells from oxidative stress induced by hydrogen peroxide. After demonstrating the non-cytotoxicity and the cytoprotective potential of the produced nanoparticles, it was evaluated if this nanosystem could be absorbed into the gastrointestinal system. Results evidenced the presence of voluminous multivesicular bodies in the enterocyte's periapical cytoplasm, suggesting an increase in the absorptive capacity of these cells. Furthermore, a significant enlargement of the apical intercellular space was observed, indicating a possible absorption of acGCP@EO nanoparticles via paracellular transport. The biological potential of the produced acCGP@EO nanoparticles was assessed by evaluating their effect in an animal model of hypertension. The antihypertensive activity was assessed using normotensive Wistar rats and Spontaneously Hypertensive Rats (SHR) treated for 30 days with free essential oil or acCGP@EO in a dosage of 75 mg/kg. During treatment, the systolic blood pressure was monitored weekly by tail-cuff plethysmography. At the end of the treatment, water and food intake, as well as urine and feces excretion, were evaluated. Biochemical and histopathological tests were conducted to evaluate the cardiometabolic effect of the treatment. To assess the nephroprotective potential of the treatments, plasmatic and urinary levels of creatinine, urea, uric acid, total proteins, sodium, and potassium were measured. Hepatic and renal tissues were also analyzed in terms of their histopathological and immunohistochemical characteristics. The results demonstrated that the acCGP@EO nanoparticles effectively encapsulated the essential oil from C.sinensis, achieving an encapsulation efficiency of 75.18% and a hydrodynamic diameter of 161 nm. The polydispersity index was found to be 0.141, indicating a monodisperse nanosystem. The zeta potential was -19.17 mV, indicating a negative superficial charge that is attributed to the intrinsic characteristics of the acCGP molecule. Results from systolic blood pressure evidenced that EO and acCGP@EO had significant anti-hypertensive effects. The analysis of the plasma and urinary metabolites evidenced that EO and acCGP@EO nanoparticles promoted natriuresis without altering the plasmic levels of sodium, suggesting improvement of renal function. Results also evidenced a recovery of the glomerular filtration rate in the SHR animals treated with accGP@EO, confirmed by increased creatinine and urea clearance. This result highlights the best performance of the nanosystem compared to the non-nanostructured EO. The treatment with acCGP@EO nanoparticles was also efficient in reducing the lipidic peroxidation in the kidney and liver tissues. Treatment with EO and acCGP@EO nanoparticles was also efficient in increasing superoxide dismutase and catalase activity in the kidney and liver tissues of the SHR animals. Immunohistochemistry findings indicated a more pronounced anti-inflammatory effect of acCGP@EO nanoparticles in reducing hepatic and renal TNFα levels in SHR animals, demonstrating the nephroprotective and hepatoprotective potential of the produced nanoparticles. Altogether, results demonstrate that the proposed nanoparticle production methodology was effective, and the nanoencapsulation improved the bioactive potential of essential oil from Citrus sinensis, promoting absorption in the gastrointestinal tract, as well as antihypertensive, anti-inflammatory, nephroprotective, and hepatoprotective effects
Suscetibilidade de fases perinatais no desenvolvimento de doenças cardiometabólicas: a puberdade como período de manifestação de sintomas
(Universidade Federal de Goiás, 2023-09-18) Ferreira Junior, Marcos Divino; Matafome, Paulo Nuno Centeio; Custódio, Carlos Henrique Xavier; http://lattes.cnpq.br/0207928273284808; Gomes, Rodrigo Mello; http://lattes.cnpq.br/3121095341590269; Gomes, Rodrigo Mello; Boschero, Antonio Carlos; Mathias, Paulo Cezar de Freitas; Silva, Patrícia Cristina Lisbôa da; Taylor, Paul David
Understanding how susceptibility in the early stages of life can predispose an individual to a greater risk of developing long-term diseases is the focus of DOHaD studies. The main aim of this thesis is to highlight the importance of early assessment of the effects of harmful stimuli suffered in the early stages of life. Given the subtlety of these short-term effects, most studies focus on studying these effects when they have already been consolidated. Here, we open up a new discussion on puberty as the initial period of symptom onset, and also as a favourable time to establish strategies to mitigate the damage already known in adulthood. To this end, we evaluated the effects of maternal exposure to methylglyoxal on metabolic and cardiovascular parameters in young Wistar rat offspring, and also assessed the contribution of growth hormone secretagogue hormone receptor (GHSR) signalling during perinatal stages on neurodevelopment and energy metabolism in young animals. In both studies, the focus was on evaluating several parameters during the pubertal phase. As main findings, we demonstrated that early exposure to glycotoxins led to cardiac and vascular deficiencies, and that modulation of the GHSR receptor in perinatal stages can affect glucose homeostasis. Throughout life, these effects can become more harmful, leading to heart failure or serious metabolic diseases such as non-alcoholic fatty liver disease. This highlights the importance of puberty as a stage for surveillance and intervention.
Efeitos cardiometabólicos e renais de peptídeos bioativos do feijão comum (phaseolus vulgaris)
(Universidade Federal de Goiás, 2022-08-18) Ribeiro, Juliana Vila Verde; Batista, Karla de Aleluia; http://lattes.cnpq.br/9859814532588957; Custódio, Carlos Henrique Xavier; http://lattes.cnpq.br/0207928273284808; Custodio, Carlos Henrique Xavier; Batista, Karla de Aleluia; Torsoni , Marcio Alberto; Sant'Ana, Anderson de Souza; Gomes, Rodrigo Mello
The common bean is susceptible to the hardening process and once hardened, it is not commercialized, being considered an agroindustry residue. However, it is possible to use it as a source of proteins and bioactive peptides. The bean bioactive peptides may have antihypertensive, antihyperglycemic, hypoglycemic, antioxidant and hypocholesterolemic activity. Thus, this work sought to study the bioactivity of the low molecular weight peptide fraction extracted from hardened common bean (Phaseolus vulgaris) grains on renal, cardiovascular and metabolic functions. To evaluate the effect of the common bean peptide, the following methodologies were used: I) Obtaining the extract and peptide fraction – from the hardened beans, flour was made using a knife mill. This flour was used to extract the peptides and proteins, using a combined solution of acetonitrile, water and formic acid (25: 24: 1), this extract was subjected to the fractionation process, using a 3 kDa filtration membrane, this extract was named as PV3. II) Comparison of PV3 amino acid sequences with other amino acid sequences reported by other authors. III) Evaluation of osmolarity and sodium and potassium ions in the PV3 extract. IV) Evaluation of the vasorelaxant effect and physiological mechanisms involved in vasorelaxation in renal artery rings from normotensive (Wistar) and hypertensive (SHR) animals. V) Evaluation of renal parameters in WT and SHR animals. VI) Evaluation of hemodynamic parameters in WT and SHR. VII) Evaluation of body mass gains and food consumption in C57BL6/6J mice submitted to a high-fat diet and administration of PV3 by pseudogavem. VIII) Assessment of glycemic levels, pyruvate, insulin and pyruvate tolerance test. IX) Evaluation of the mechanisms involved in PV3 in the insulin pathway by Western Blotting and qPCR. X) evaluation of the energy metabolism of PV3 by q PCR. The main results of this study are: I) homology of amino acid sequences of PV3 with several amino acid sequences described in the literature that show antihypertensive activity, II) PV3 causes a relaxing effect dependent on the endothelium and oxidonitrergic pathways; III) PV3 caused a natriuretic effect and decreased the glomerular filtration rate; IV) PV3 caused a hypotensive effect that was concomitant to a reduction in vascular resistance in the aortic and renal vascular beds; V) PV3 prevented the damage caused by the hyperlipidic diet, such as reduction of adiposity and glycemic levels.; VI) PV3 acts on the IRS/PI3K and AMPK pathway to reduce glycemic levels; 22 VII) PV3 acts in the regulation of energy balance. Such findings are relevant for the molecular and physiological study of bioactive peptides of food origin; and these results contribute to the use of hardened beans in the formulation of nutraceutical foods to treat hypertension, type 2 diabetes and obesity.
Análise metabólica em ratos Wistar submetidos à dessincronização circadiana forçada e alimentação em tempo restrito
(Universidade Federal de Goiás, 2023-01-26) Oliveira, Isis Gabrielli Barbieri de; Rosa, Daniel Alves; http://lattes.cnpq.br/5848020104921718; Rosa, Daniel Alves; Pansani, Aline Priscila; Araújo, John Fontenele; Torsoni, Marcio Alberto; Iglesia, Horacio de la
The suprachiasmatic nucleus is part of a multi-oscillatory timing system in mammals, regulating various physiological rhythms and under modulation by internal or environmental synchronizers, among them: the light-dark cycle (LD), the most important photic synchronizer of this system. However, non-photic synchronizers such as food availability remain more unclear. Here, we use Wistar rats (250-300g) randomly distributed into four groups: control CTR AL under a symmetrical cycle of 12:12h LD and ad libitum food availability or CTR RF with time-restricted feeding (TRF); DSC AL submitted to the forced circadian desynchronization protocol under a symmetrical cycle of 11:11h LD with ad libitum food availability and DSC RF with TRF, during eight weeks to evaluate the impact of DSC and TRF on locomotor activity, hepatic metabolism and on the antioxidant system. During the eighth week, all animals were submitted to the insulin and glucose tolerance test – ipITT and oGTT. After 48h of recovery, they were euthanized. Plasma, liver and hypothalamus samples were removed and stored for biochemical analyses, Western blotting and RT-qPCR. Results: As expected, all DSC animals showed dissociation of the locomotor activity rhythm. TRF increased the rate of dyssynchrony in the DSC RF group, indicating dominance of the light-entrained component (LEC). DSC or TRF separately did not alter total food intake or body mass, but the association of both included total food intake, reflecting on the evolution of body mass. However, the separate analysis of food intake in the LD phases demonstrates that in the light phase intake is higher in the DSC group when compared to the CTR AL.TRF promotes simultaneous increase of NPY and CART only in animals under LD cycle 12:12h. DSC increased DSC increased the gene expression of PTEN, PTPN1 and G6Pase, the PI3K protein, the activity of SOD-1 and catalase enzymes and the oxidative stress biomarkers TBARS and protein carbonyl in the liver, but TRF attenuated only the effects on G6Pase and PI3K. Conclusion: In summary, these findings show that forced desynchronization increases considerable oxidative stress and promotes changes in insulin signaling in liver, which were not attenuated by the association with TRF
Efeito tipo-antidepressivo do derivado piperazínico 2,6-di-terc-butil-4-((4-(2-hidroxietil)piperazina-1-il)metil)fenol (LQFM212) e possíveis mecanismos de ação envolvidos
(Universidade Federal de Goiás, 2023-02-27) Moreira, Lorrane Kelle da Silva; Costa, Elson Alves; http://lattes.cnpq.br/2607893423583912; Costa, Elson Alves; Fajemiroye, James Oluwagbamigbe; Ghedini, Paulo César; Rocha, Fábio Fagundes da; Carvalho, Pablinny Moreira Galdino de
Depressive disorders affect individuals worldwide and may also be associated with other mental disorders such as anxiety disorders. Despite advances to improve understanding of the neurobiology of depressive disorders, no single established mechanism per se can explain all facets of these disorders and the available drugs often show therapeutic delay for clinical effectiveness. A plethora of results show the effects of piperazine derivatives on the central nervous system and are indicators of its therapeutic potential for treating mental disorders. Previously, it was shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABAA receptor, without cognitive impairments. In this regard, since the same compound can have anxiolytic as well as antidepressant effects, the aim of this research was to evaluate the possible antidepressant-like activity of the compound LQFM212. Swiss albino male mice orally treated with LQFM212 (54 μmol/kg) showed behavioral effects related to antidepressant-like activity, in the forced swimming test (FST), after treatment with a single dose or with repeated doses for 15 consecutive days. Pretreatment with WAY-100635 (0.7 μmol/kg), p-chlorophenylalanine (500 μmol/kg), prazosin (2.6 μmol/kg), SCH-23390 (15 μg/kg), sulpiride (146 μmol/kg) ou α-methyl-p-tyrosine (512 μmol/kg) reversed the antidepressant-like effect of LQFM212 in the FST. Furthermore, repeated treatment with LQFM212 increased hippocampal brain-derived neurotrophic factor (BDNF) levels. Regarding the monitoring of body weight and the evaluation of possible biochemical changes the treatment with repeated doses with LQFM212 (54 μmol/kg) did not change: animals' body weight, liver glutathione (GSH) levels, and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine. A possible action of the compound LQFM212 on inflammatory parameters, in mice, was evaluated by systemic inflammation by the lipopolysaccharide (LPS)-induced neuroinflammation model and by local inflammation by the carrageenan- or LPS-induced pleurisy model. In the LPS-induced neuroinflammation model, oral treatment with LQFM212 (54 μmol/kg) reversed the anxiety-like and depression-like behaviors, in the open field, forced swimming and tail suspension tests, the increase of pro-inflammatory cytokines (TNF-α and IL-1β) and the decrease of anti-inflammatory cytokines (IL-4 and IL-10), into animals’ serum, caused by intraperitoneal administration of LPS (1 mg/kg). In this same model, treatment with LQFM212 (54 μmol/kg) also attenuated oxidative stress-related changes, demonstrated by reduced nitrite levels and myeloperoxidase (MPO) activity, and increased glutathione levels in the prefrontal cortex and hippocampus, and also reduced cholinesterase activity in the whole brain, of animals that received intraperitoneal administration of LPS (1 mg/kg). On the other hand, oral treatment with LQFM212 (54 μmol/kg) failed to reduce the increase in cell migration and pro-inflammatory cytokines (TNF-α and IL-1β) in pleural exudate caused by intrapleural administration of 1% carrageenan or LPS (250 ng/mL) in the pleurisy model. In addition to the reduction in MPO activity seen in the LPS-induced neuroinflammation model, treatment with LQFM212 (54 μmol/kg) also reduced the activity of this enzyme in the pleural exudate of animals subjected to the carrageenan- or LPS-induced pleurisy model. Taken together, the results showed that treatment with LQFM212 promotes behavioral changes suggestive of antidepressant-like activity in mice, which probably involve the monoaminergic pathways, in addition to increased hippocampal levels of BDNF, suggesting changes in synaptic neuroplasticity possibly as a mechanism underlying the antidepressant-like effect of the compound. The effects found in the LPS-induced neuroinflammation model did not seem to be secondary to a peripheral anti-inflammatory action of LQFM212, since this compound failed to reduce the changes caused by carrageenan or LPS in the pleurisy model. On the other hand, treatment with LQFM212 reduced MPO enzyme activity in pleural exudate, prefrontal cortex, and hippocampus, and increased per se GSH levels in both brain regions mentioned above, thus suggesting a possible antioxidant activity in vivo that may contribute to the effects observed in the neuroinflammation and pleurisy model.
Avaliação das atividades genotóxica, antigenotóxica, angiogênica e potencial de cicatrização do látex da Synadenium umbellatum Pax
(Universidade Federal de Goiás, 2009-11-27) Reis, Paulo Roberto de Melo; Lee, Chen Chen; http://lattes.cnpq.br/4621907105842007
Synadenium umbellatum Pax (1894) is a vegetable species from Euphorbiaceae‟s family. The species of this family produce latex. The latex extracted from S. umbellatum has been used by the Brazilian people as anti-tumoral, anti-inflammatory and wound healing agents. However, this latex presents toxic substances and proteolic enzymes. The aim of this work was to evaluate the possible genotoxic, antigenotoxic, cytotoxic, angiogenic and wound healing activities of S. umbellatum latex (SuL) in rats. The genotoxic and antigenotoxic activities were evaluated by mouse bone marrow micronucleus test. An alkylant agent mitomycin C (4 mg.kg-1 body weight) was used as a positive control. For all doses, micronucleated polychromatic erythrocytes (MNPCE) frequency was evaluated after 24 hours of treatment. To evaluate the antimutagenic activity, animals were treated with 10, 30, 50 and 100 mg.kg-1 and 4 mg. kg-1 of mitomycin C (MMC) simultaneously. The frequency of MNPCE was evaluated 24 hours after exposure. Cytotoxicity was evaluated by the polychromatic and normochromatic erythrocytes ratio (PCE/NCE). Angiogenic activity of the SuL was evaluated in chorioallantoic membrane (CAM) of fertilized chicken eggs. The concentrations of the SuL were of 10 and 20 mg/mL. Wound healing activity was evaluated in skin of rats. The skin fragment was removed with area 3 x 2,5 cm and submitted to topic application with 5 mL of SuL (concentration 10 mg/mL) and positive and negative controls. The results showed that the SuL was strongly mutagenic, cytotoxic, and antimutagenic, and a moderate activity of anticytotoxicity. In the evaluation of the angiogenesis, the SuL has promoted the increase of the proliferation of blood vessels in the chorioallantoic xvii membrane of fertilized chicken eggs and it also induced the increase of velocity of wound healing in rat skin lesion.
O-GlcNAcilação de proteínas como um sensor de nutrientes sinalizando disfunção placentária na gestação hipertensiva
(Universidade Federal de Goiás, 2022-11-30) Passos Junior, Rinaldo Rodrigues dos; Vitorino, Fernanda Regina Casagrande Giachini; http://lattes.cnpq.br/3100345884689140; Vitorino, Fernanda Regina Casagrande Giachini; Martín, Sebastián San; Fagundes, Danny Laura; Biancardi, Manoel Francisco; Gomes, Rodrigo Mello
The protein O-GlcNAcylation is essential for a proper placental development and this post-translational modification is found to be disrupted in hypertensive disorders of pregnancy. The present study aimed to investigate the impact of hypertension on the protein O-GlcNAcylation and fetal-placental development throughout pregnancy. First, a non-systematic literature review was carried out, based on analyzes and interpretations of the existing scientific production to understand the involvement of OGlcNAc in the establishment of hypertension. Subsequently, we sought to characterize how O-GlcNAcylation of proteins affects placental function and fetal growth throughout pregnancy under hypertensive conditions. To achieve this, spontaneously hypertensive rats (SHR) and Wistar were divided into 14, 17, and 20 days of pregnancy (DOP) groups. On the 14th, 17th, and 20th DOP, placentas were collected and submitted to western blot, immunohistochemistry, and morphological analysis. OGlcNAc protein expression was lower in placentas from SHR compared to Wistar at 14 (p=0.003) and 20 DOP (p<0.0001). Reduced OGT (p=0.01) and OGA (p=0.002) enzymes expression was found on 14 DOP in SHR. Increased pre-implantation losses were found in SHR at 14, 17, and 20 DOP. SHR presented reduced fetal weight and increased small for gestational age fetuses on all DOP analyzed. Placental weight was increased in near-term SHR (p=0.006) whereas placental efficiency was decreased in SHR at 17 (p=0.01) and 20 DOP (p<0.0001). Morphological analysis showed reduced junctional zone area and labyrinth vasculature alterations on placentas from SHR in all DOP analyzed. Reduced placental O-GlcNAc content was found in both the junctional zone and labyrinth of the placentas from SHR. Decreased glycogen cell content in placental tissue from SHR at 14, 17, and 20 DOP. Moreover, GLUT1 expression was found to be decreased in placentas from SHR in all DOP. Collectively, these findings suggest that reduced protein O-GlcNAcylation, resulting from decreased placental nutritional apport, contributes to placental structural and functional derangement during hypertensive pregnancy, impairing fetal growth.
Contribuição da neurotransmissão glutamatérgica na região rostroventrolateral do bulbo (RVLM) para as respostas cardiovasculares e autonômicas induzidas pelo fator de necrose tumoral alfa (TNF-α) no núcleo paraventricular do hipotálamo (PVN)
(Universidade Federal de Goiás, 2022-10-31) Naves, Lara Marques; Pedrino, Gustavo Rodrigues; http://lattes.cnpq.br/1155446449250341; Pedrino, Gustavo Rodrigues; Custódio, Carlos Henrique Xavier; Fajemiroye, James Oluwagbamigbe; Mourão, Aline Andrade; Oliveira, André Henrique Freiria de
Neurogenic hypertension is characterized by a chronic elevation of blood pressure (BP) associated with exacerbation of sympathetic nerve activity (SNA). In this sense, the neuroinflammation, marked by the presence of pro-inflammatory cytokines (PIC) in the central nervous system (CNS), can be related to increased sympathetic drive and arterial hypertension (AH) development. Furthermore, the presence of tumor necrosis factor alpha (TNF-α) in sympathetic premotor neurons that compose the rostral ventrolateral medulla (RVLM) and hypothalamic paraventricular nucleus (PVN) is associated with hypertensive phenotype. However, the pathways and mechanisms by which TNF-α act in the CNS remain under investigation. Thus, the present study investigated the cardiovascular and autonomic effects promoted by TNF-α administration in the PVN and the participation of glutamatergic neurotransmission and N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the RVLM in these responses. For this, Wistar and spontaneously hypertensive rats (SHR) (270 - 300g) were anesthetized with urethane (400 mg/mL, intravenous - i.v.) associated with α-chloralose (40 mg/mL, i.v.) and instrumented to mean arterial pressure (MAP), heart rate (HR) and splanchnic sympathetic nervous activity (SSNA) recordings. The animals were organized into five groups and subjected to unilateral nanoinjections (50 nL) in the RVLM as follows: I. Wistar subjected to vehicle nanoinjections (Ringer's solution, normotensive SHAM group, n=5); II. SHR subjected to vehicle nanoinjections (Ringer's solution, hypertensive SHAM group, n=7); III. SHR subjected to kynurenic acid nanoinjections (KYN, 50 mM, glutamate receptor antagonist, hypertensive GLU group, n=6); IV. SHR subjected to 2-amino-5-phosphonovaleric acid nanoinjections (AP5, 24 nmol/50 nL, NMDA receptor antagonist, hypertensive NMDA group, n=7) and V. SHR subjected to 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f] quinoxaline nanoinjections (NBQX, 5.2 nmol/50 nL, AMPA receptor antagonist, hypertensive AMPA group, n=6). Then, all groups were subjected to ipsilateral TNF-α nanoinjections (0.6 pmol/50 nL, 50 nL) in the PVN. Nanoinjections of vehicle, KYN, AP5 or NBQX in RVLM did not change baseline values of MAP, HR and SSNA. In the normotensive SHAM group, TNF-α nanoinjections into the PVN induced an ANSE increase after 50 min of TNF-α nanoinjections, without modifying the MAP and HR. In contrast, in the hypertensive SHAM group, TNF-α nanoinjections in the PVN promoted a progressive splanchnic sympathoexcitation initiated 20 min after the TNF-α nanoinjections. After 50 min of TNF-α nanoinjections, a pressor response was observed, without changing HR, in the hypertensive SHAM group. Previous inhibition of RVLM glutamatergic neurotransmission did not alter the pressor response induced by TNF-α in hypertensive animals and did not change the HR. However, abolished the splanchnic sympathoexcitation observed after TNF-α. Additionally, NMDA or AMPA receptors previous inhibition in RVLM was not able to change the TNF-α-induced late increase in MAP and the HR in hypertensive animals. However, attenuated the splanchnic sympatoexcitation generated after the TNF-α nanoinjections. These results suggest that cardiovascular and autonomic changes promoted by TNF-α in the PVN are exacerbated in hypertensive animals and that the integrity of glutamatergic neurotransmission and NMDA and AMPA receptors in the RVLM are essential for the sympathoexcitatory response induced by TNF-α in the PVN in SHR.
Efeito neuroprotetor e antiepiléptico da infusão intracerebroventricular crônica de angiotensina-(1-7) em ratos com epilepsia do lobo temporal
(Universidade Federal de Goiás, 2020-03-02) Gomes, Karina Pereira; Castro, Carlos Henrique de; http://lattes.cnpq.br/6354834854727314; Colugnati, Diego Basile; http://lattes.cnpq.br/3875833705952056; Colugnati, Diego Basile; Torres, Bruno Benetti Junta; Pedrino, Gustavo Rodrigues; Blanch, Graziela Torres; Menegatti, Ricardo
Epilepsy is a severe neurological disorder characterized by permanent predisposition of the brain to generate spontaneous and recurrent seizures. Temporal Lobe Epilepsy (TLE) is the most frequent type of epilepsy in adults and is often refractory to pharmacological treatments available. Recently, several neuropeptides and their receptors have been suggested as promising therapeutic targets for the treatment of epilepsy, including neuropeptides and receptors of the Renin Angiotensin System (RAS). The aim of this study was to evaluate the effects of chronic treatment with Angiotensin-(1-7) (Ang-(1-7)) in male Wistar rats with TLE. The Pilocarpine (PILO) model was used for TLE induction and after the first spontaneous seizure, the animals were submitted to stereotactic surgery for implant of a guide cannula attached to an osmotic minipump. Rats of control group (CT) underwent the same procedures as the rats of groups with epilepsy, but were resistant to PILO model, not developing ELT. Intracerebroventricular infusion of Ang-(1-7) (200ng/kg/h) or sterile saline solution (NaCl 0.9%) was performed for 30 days and body weight, feed intake and spontaneous seizures were evaluated. At the end of the treatment, behavioral tests were performed in Elevated Plus Maze (EPM) and Open Field (OF) for evaluation of anxiety-like behavior and locomotor/exploratory activity. In the next day after behavioral tests, the animals were euthanized and the hippocampus were dissected, stored and later processed for protein analysis using Western Blot technique. For RAS components investigation, protein levels of Angiotensin Converting Enzyme 2 (ACE2) and Neutral Endopeptidase (NEP), as well as AT1, AT2 and Mas receptors were evaluated. In addition, hippocampal levels of Interleukin-6 (IL-6), Superoxide Dismutase (SOD), Catalase (CAT), B-Cell Lymphoma 2 (Bcl-2) and the phosphorylation of Mammalian Target of Rapamycin (mTOR) were quantified. Chronic intracerebroventricular treatment with Ang-(1-7) significantly reduced the frequency of spontaneous epileptic seizures, mainly at light photoperiod of the light-dark cycle, without changing its duration. Saline treated TLE rats (EP) showed significantly lower body weight gain than control rats without epilepsy (CT), which was attenuated in the last two weeks by Ang- (1-7) treatment (EP + Ang-(1-7)). However, the feed intake did not differ among evaluated groups. The time spent in EPM open arms by EP group was significantly higher than CT group, an effect attenuated by Ang-(1-7) treatment. In addition, the total number of entries in EPM arms was higher in EP group, which was reversed in EP + Ang-(1-7) group. The number of crossings in OF was significantly higher in EP group, which was reversed by Ang-(1-7) treatment. However, the immobility time and the numbers of rearing, also increased in the EP group, were only attenuated by Ang-(1- 7) treatment. Our results, revealed that Ang-(1-7) positively regulated the antioxidant protein CAT, the anti-apoptotic protein Bcl-2 and also increased the phosphorylation of anti-apoptotic protein mTOR, all reduced by epilepsy in hippocampus. In addition, the upregulation of AT1 receptor induced by TLE in hippocampus was also attenuated by treatment with Ang-(1-7). The protein levels of ACE2, NEP and SOD enzymes, as well as AT2 receptor and IL-6 were not statistically different between the groups. Mas receptor was downregulated in hippocampus of EP + Ang-(1-7) group. Our data suggest that Ang-(1-7) has direct modifying effects on chronic TLE by reducing oxidative stress and hippocampal neuronal death. From these results we can conclude that chronic intracerebroventricular treatment with Ang-(1-7) in rats with PILO induced- TLE reduces hippocampal neuronal damage and the frequency of spontaneous seizures, attenuating the damage in body weight gain and behavioral abnormalities. This study provides evidence that Ang-(1-7) and its receptor are promising targets for the treatment of TLE and its comorbidities.

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