Papel do extrato etanólico bruto de Trichoderma stromaticum na infecção de camundongos C57BL/6 por Plasmodium berghei ANKA

Malaria is a severe health problem. The first-line treatment against the disease are the artemisinin-based combination therapies. However, increased resistance to these drugs has been reported. The aim of this study was to evaluate the role of crude etanolic extracts of Trichoderma stromaticum (Ext-Ts) in C57BL/6 mice infected with Plasmodium berghei ANKA, a well-known model of experimental cerebral malaria. Clinical, histological, immunological and biochemical features of the infection were monitored. It was found that Ext-Ts treatment was able to prevent neurological alterations associated with experimental cerebral malaria, decreased parasitemia levels and significantly improved survival of infected animals. Furthermore, it was observed that in Ext-Ts-treated mice a reduction of total serum cholesterol, triglycerides and TGP, lower hemozoin deposition into the liver, attenuation of pulmonary edema intensity, integrity of the blood-brain barrier as well as fewer cytoadherence and histopathological findings in assessed tissues in comparison with untreated infected mice. This protection was associated with decreased IFN-γ and ICAM-1 mRNA expression in brain of treated animals compared with untreated animals. These results suggest that Ext-Ts is a potential source of antimalarial and immunomodulatory compounds that could improve the current treatment in the context of resistance to artemisinin derivatives.CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCNPq - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas GeraisDissertação (Mestrado)A malária é um grave problema de saúde pública. Os medicamentos de escolha para tratar a doença são as terapias baseadas em combinações de artemisininas. Porém, uma crescente resistência à estas drogas tem sido reportada. A presente investigação teve como objetivo avaliar o papel do extrato etanólico bruto de Trichoderma stromaticum (Ext-Ts) em camundongos C57BL/6 infectados com Plasmodium berghei ANKA, um conhecido modelo experimental de malária cerebral experimental. Foram monitoradas as manifestações clinicas, histológicas, imunológicas e bioquímicas características da infecção. Observou-se que o tratamento com Ext-Ts foi capaz de prevenir as alterações neurológicas associadas à malária cerebral experimental, diminuir os níveis de parasitemia e aumentar significativamente a sobrevivência de animais infectados. Além disso, foi observado que em camundongos tratados com Ext-Ts houve diminuição dos níveis de colesterol total, triglicerídeos e TGP no soro, menor deposição de hemozoína no fígado, atenuação da intensidade do edema pulmonar, proteção da integridade da barreira hematoencefálica, assim como menor citoaderência e achados histopatológicos nos tecidos avaliados, quando comparado com camundongos infectados não tratados. Esta proteção foi associada com uma diminuição na expressão de IFN-γ e ICAM-1 no cérebro dos animais tratados em relação a animais não tratados. Estes resultados sugerem que o Ext-Ts é uma potencial fonte de compostos antimaláricos e/ou imunomoduladores que poderiam melhorar o tratamento atual no contexto do aumento da resistência aos derivados da artemisinina

A comparison of rat models that best mimic immune-driven preeclampsia in humans

Preeclampsia (PE), a hypertensive pregnancy disorder, can originate from varied etiology. Placenta malperfusion has long been considered the primary cause of PE. However, we and others have showed that this disorder can also result from heightened inflammation at the maternal-fetal interface. To advance our understanding of this understudied PE subtype, it is important to establish validated rodent models to study the pathophysiology and test therapies. We evaluated three previously described approaches to induce inflammation-mediated PE-like features in pregnant rats: 1) Tumor necrosis factor-α (TNF-α) infusion via osmotic pump from gestational day (GD) 14-19 at 50ng/day/animal; 2) Polyinosinic:polycytidylic acid (Poly I:C) intraperitoneal (IP) injections from GD 10-18 (alternate days) at 10mg/kg/day/animal; and, 3) Lipopolysaccharide (LPS) IP injections from GD 13-18 at 20ug-70ug/kg/day per animal. Maternal blood pressure was measured by tail-cuff. Upon sacrifice, fetal and placenta weights were recorded. Placenta histomorphology was assessed using H&E sections. Placenta inflammation was determined by quantifying TNF-α levels and inflammatory gene expression. Placenta metabolic and mitochondrial health were determined by measuring mitochondrial respiration rates and placenta NAD+/NADH content. Of the three rodent models tested, we found that Poly I:C and LPS decreased both fetal weight and survival; and correlated with a reduction in region specific placenta growth. As the least effective model characterized, TNF-α treatment resulted in a subtle decrease in fetal/placenta weight and placenta mitochondrial respiration. Only the LPS model was able to induce maternal hypertension and exhibited pronounced placenta metabolic and mitochondrial dysfunction, common features of PE. Thus, the rat LPS model was most effective for recapitulating features observed in cases of human inflammatory PE. Future mechanistic and/or therapeutic intervention studies focuses on this distinct PE patient population may benefit from the employment of this rodent model of PE

DataSheet_1_A comparison of rat models that best mimic immune-driven preeclampsia in humans.pdf

Preeclampsia (PE), a hypertensive pregnancy disorder, can originate from varied etiology. Placenta malperfusion has long been considered the primary cause of PE. However, we and others have showed that this disorder can also result from heightened inflammation at the maternal-fetal interface. To advance our understanding of this understudied PE subtype, it is important to establish validated rodent models to study the pathophysiology and test therapies. We evaluated three previously described approaches to induce inflammation-mediated PE-like features in pregnant rats: 1) Tumor necrosis factor-α (TNF-α) infusion via osmotic pump from gestational day (GD) 14-19 at 50ng/day/animal; 2) Polyinosinic:polycytidylic acid (Poly I:C) intraperitoneal (IP) injections from GD 10-18 (alternate days) at 10mg/kg/day/animal; and, 3) Lipopolysaccharide (LPS) IP injections from GD 13-18 at 20ug-70ug/kg/day per animal. Maternal blood pressure was measured by tail-cuff. Upon sacrifice, fetal and placenta weights were recorded. Placenta histomorphology was assessed using H&E sections. Placenta inflammation was determined by quantifying TNF-α levels and inflammatory gene expression. Placenta metabolic and mitochondrial health were determined by measuring mitochondrial respiration rates and placenta NAD+/NADH content. Of the three rodent models tested, we found that Poly I:C and LPS decreased both fetal weight and survival; and correlated with a reduction in region specific placenta growth. As the least effective model characterized, TNF-α treatment resulted in a subtle decrease in fetal/placenta weight and placenta mitochondrial respiration. Only the LPS model was able to induce maternal hypertension and exhibited pronounced placenta metabolic and mitochondrial dysfunction, common features of PE. Thus, the rat LPS model was most effective for recapitulating features observed in cases of human inflammatory PE. Future mechanistic and/or therapeutic intervention studies focuses on this distinct PE patient population may benefit from the employment of this rodent model of PE.</p

Image_2_A comparison of rat models that best mimic immune-driven preeclampsia in humans.jpeg

Preeclampsia (PE), a hypertensive pregnancy disorder, can originate from varied etiology. Placenta malperfusion has long been considered the primary cause of PE. However, we and others have showed that this disorder can also result from heightened inflammation at the maternal-fetal interface. To advance our understanding of this understudied PE subtype, it is important to establish validated rodent models to study the pathophysiology and test therapies. We evaluated three previously described approaches to induce inflammation-mediated PE-like features in pregnant rats: 1) Tumor necrosis factor-α (TNF-α) infusion via osmotic pump from gestational day (GD) 14-19 at 50ng/day/animal; 2) Polyinosinic:polycytidylic acid (Poly I:C) intraperitoneal (IP) injections from GD 10-18 (alternate days) at 10mg/kg/day/animal; and, 3) Lipopolysaccharide (LPS) IP injections from GD 13-18 at 20ug-70ug/kg/day per animal. Maternal blood pressure was measured by tail-cuff. Upon sacrifice, fetal and placenta weights were recorded. Placenta histomorphology was assessed using H&E sections. Placenta inflammation was determined by quantifying TNF-α levels and inflammatory gene expression. Placenta metabolic and mitochondrial health were determined by measuring mitochondrial respiration rates and placenta NAD+/NADH content. Of the three rodent models tested, we found that Poly I:C and LPS decreased both fetal weight and survival; and correlated with a reduction in region specific placenta growth. As the least effective model characterized, TNF-α treatment resulted in a subtle decrease in fetal/placenta weight and placenta mitochondrial respiration. Only the LPS model was able to induce maternal hypertension and exhibited pronounced placenta metabolic and mitochondrial dysfunction, common features of PE. Thus, the rat LPS model was most effective for recapitulating features observed in cases of human inflammatory PE. Future mechanistic and/or therapeutic intervention studies focuses on this distinct PE patient population may benefit from the employment of this rodent model of PE.</p