Programa de Pós-graduação em Ciências Biológicas

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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.
Criação de modelo de neuroesfera a partir de células-tronco da polpa dentária para o estudo de Hemiplegia Alternante da Infância
(Universidade Federal de Goiás, 2024-12-05) Cunha, Júlia Cristina Lucio da; Leite, Jacqueline Alves; http://lattes.cnpq.br/0714922922038212; Leite, Jacqueline Alves; Cortes, Vanessa Faria; Carvalho, Renata Karine de
Embargado.
Estudo da atividade tipo-ansiolítica das folhas de Pimenta pseudocaryophyllus (Gomes) L.R. Landrum - Myrtaceae
(Universidade Federal de Goiás, 2012) Fajemiroye, James Oluwagbamigbe; Costa, Elson Alves
Pimenta pseudocaryophyllus, popularly known as Craveiro, is the only species in this genus native to the cerrado of Brazil. Ethnopharmacological studies revealed medicinal use of P. pseudocaryophyllus extracts in treating menstrual and digestive problems as well as emotional tension in the form of soothing tea among other therapeutic applications in Brazilian folk medicine. Its popular use is of great interest given the alarming increase in neural diseases and search for innovative herbal therapy. For the purpose of this study, the ethanolic leaf extract of Pimenta pseudocaryophyllus (EEPp) was obtained by soaking the dried leaf powder in ethanol (95%, 1:5). The fractions of hexane (FH), dichloromethane (DF), ethyl acetate (EAF) and aqueous (AF) were subsequently prepared through EEPp fractionation with solvents of different polarities. Mice weighing between 25 - 35g were treated acutely (sc / p.o / i.p) for the general test of pharmacological activity while oral administration was later explored for most of the central action screening considering lack of any sign of neurotoxicity even at the highest dose (2 g/Kg). Sleep induced by barbiturates was potentiated by the ethanolic leaf extract (1 g/Kg) through prolongation of sleeping time (duration) and reduction in time taken for the loss of righting reflex (latency). Identification of the active fraction of this extract was performed using behavioural models, such as sleep induced, open field, light / dark box test (LDB) and elevated plus maze (EPM). In this manner, only EAF (0.42 g/Kg) and HF treatments did not increase sleep duration and failed to demonstrate anxiolytic like effect. Meanwhile, treatment with DF (0.25 g/Kg) and AF (0.64 g/Kg) showed an increase in sleep duration and significant alterations of time and number of crossing at the centre of the open field. The AF demonstrated sedative effect in the LDB. Meanwhile, the DF (0.125, 0.25 or 0.5 g/Kg) showed anxiolytic like activity in both the LDB and EPM in a dose- dependent manner. These results suggested the presence of active principles of the P. pseudocaryophyllus that may be useful in developing a drug for the treatment of anxiety. It is worthy to state that no sign of neurotoxicity or motor incoordination was observed with DF treatment. In an attempt to elucidate the mechanism of action involved, pre-treatment with flumazenil (antagonist of benzodiazepine site of GABAA receptor) did not block anxiolytic-like effect of DF thereby excluding the participation of this site. However, this effect was reversed by pretreatment with NAN-190 (an antagonist of the 5-HT1A). This result suggests a possible involvement of the serotonergic system. In this case the results obtained on the neuropharmacological activity of dichloromethane fraction showed promising effect in anxiety model which require further extensive study to characterize neurobiological pathways involved for possible clinical application and better understanding of the pathophysiology of this neural disorder.
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).
Avaliação da atividade anti-inflamatória e/ou antinociceptiva de duas espécies vegetais do cerrado: Lafoensia pacari A. St. Hil e Spiranthera odoratissima A. St. Hil.
(Universidade Federal de Goiás, 2011) Nascimento, Marcus Vinícius Mariano; Silva, Roberto do Nascimento; Costa, Elson Alves
The species of plants Lafoensia pacari A. St.-Hil and Spiranthera odoratissima A. Hil St., known as “pacarí” and “manacá”, respectively, are largely used in folk medicine in the state of Goiás, Brazil. This work shows the antinociceptive and anti-inflammatory effects of ethanolic extract of stem bark of “pacarí” (PEtExt) at doses of 100, 300 and 1000 mg/kg, p.o., in different models “in vivo” in mice, such as: acetic acid-induced abdominal writhing, croton oil–induced ear edema and formalin test. After the crude extract partitioning, only the ethyl acetate fraction at dose 640 mg/kg, p.o., (EAF) showed these activities. Ellagic acid at doses of (10, 30 and 100 mg/kg, p.o.) isolated from the stem bark of “pacarí”, is the substance responsible for the anti-inflammatory activity of PEtExt and EAF, however, the ellagic acid did not show antinociceptive effect on neurogenic pain formalin test. This antinociceptive activity does not involve the participation of opioid receptors, because it was not reversed by pretreatment with naloxone at dose 3 mg/kg, s.c., (opioid receptor antagonist). The results show that PEtExt and EAF have independent analgesic activity of anti-inflammatory effect of ellagic acid. This work also shows the anti-inflammatory of methanol/aqueous phase of the ethanol extract of the leaves of “manacá” at doses of 50, 150 and 500 mg/kg, p.o., (MAP) in different models “in vivo” in mice, such as: formalin test, carrageenan-induced paw oedema. Myeloperoxidase activity, capillary permeability, leukocyte migration and TNF-α levels were evaluated in pleural exudate. The reduction in the levels of TNF-α caused by treatment with MAP may be responsible for anti-inflammatory effect observed with the “manacá” plant in different models used.
Efeito neuroreparador do ácido decanoico em modelo animal de isquemia cerebral
(Universidade Federal de Goiás, 2024-02-23) Nunes, Antonio Ítalo dos Santos; Pinto, Mauro Cunha Xavier; http://lattes.cnpq.br/0868250984727943; Pinto, Mauro Cunha Xavier; Chiareli, Raphaela Almeida; Costa, Renata Mazaro e
Cerebral ischemia is a neurological disorder that occurs due to the abrupt interruption of blood flow in the brain and can result in cognitive and motor impairments. Decanoic acid has been proposed as a potential therapeutic agent in neurological diseases as it blocks AMPA receptors and acts on neuroinflammation. In this context, the aim of this study was to investigate the effect of decanoic acid in a model of cerebral ischemia by middle cerebral artery occlusion (MCAO) in mice. For this purpose, mice received different doses of decanoic acid (62.5, 125, 250, 500, and 1000 mg/kg) or vehicle by gavage for 7 or 14 days after the induction of ischemia. Morphological analysis of the ischemic area was performed by TTC staining. Motor asymmetry, postural tone, spatial and contextual memory deficits were also evaluated using the Cylinder, Limb Clasping, OLT, and NORT tests, respectively. Furthermore, investigations of the mechanisms involved in this neurorepair were carried out by ELISA technique for inflammatory biomarkers and Western Blot to analyze AMPA receptor pathways and autophagy. The results showed that, after 7 and 14 days of treatment, decanoic acid was able to promote neurorepair effects, evidenced by the reduction of the ischemic area and improvement in motor, cognitive, and memory impairments. In addition to revealing anti-inflammatory effects, reducing the expression of pro-inflammatory cytokines, and surprisingly, this effect seems not to be related to changes in the expression of AMPA receptors or the autophagy pathway. This study suggests that decanoic acid has therapeutic potential for ischemic injuries, promoting functional and cognitive recovery, as well as acting on reducing inflammation.
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.
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.

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