RESUMO
Breast cancer is the most common malignant tumor among women worldwide, and triple-negative breast cancer is the most aggressive type of breast cancer, which does not respond to hormonal therapies. The protease inhibitor, EcTI, extracted from seeds of Enterolobium contortisiliquum, acts on the main signaling pathways of the MDA-MB-231 triple-negative breast cancer cells. This inhibitor, when bound to collagen I of the extracellular matrix, triggers a series of pathways capable of decreasing the viability, adhesion, migration, and invasion of these cells. This inhibitor can interfere in the cell cycle process through the main signaling pathways such as the adhesion, Integrin/FAK/SRC, Akt, ERK, and the cell death pathway BAX and BCL-2. It also acts by reducing the main inflammatory cytokines such as TGF-α, IL-6, IL-8, and MCP-1, besides NFκB, a transcription factor, responsible for the aggressive and metastatic characteristics of this type of tumor. Thus, the inhibitor was able to reduce the main processes of carcinogenesis of this type of cancer.
Assuntos
Citocinas/antagonistas & inibidores , Fabaceae/química , Glicosaminoglicanos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Inibidores da Tripsina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Citocinas/biossíntese , Feminino , Humanos , Metaloproteinases da Matriz/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Inibidores da Tripsina/uso terapêuticoRESUMO
In vivo studies show the benefits of the trypsin inhibitor isolated from tamarind (Tamarindusindica L.) (TTI) seeds in satiety and obesity. In the present study, TTI nanoencapsulation (ECW) was performed to potentialize the effect of TTI and allow a controlled release in the stomach. The impact on glycemia, insulin, and lipid profile was evaluated in Wistar rats overfed with a high glycemic index diet (HGLI). Characterization of the nanoparticles and in vitro stability in simulated gastrointestinal conditions, monitored by antitrypsin activity and HPLC, was performed. ECW and empty nanoparticles (CW) were administered by gavage, using 12.5 and 10.0 mg/kg, respectively. Both nanoformulations presented a spherical shape and smooth surface, with an average diameter of 117.4 nm (24.1) for ECW and 123.9 nm (11.3) for CW. ECW maintained the antitrypsin activity (95.5%) in the gastric phase, while TTI was completely hydrolyzed. In Wistar rats, the nanoformulations significantly reduced glycemia and HOMA IR, and ECW increased HDL-c compared to CW (p < 0.05).Pancreas histopathology of animals treated with ECW suggested an onset of tissue repair. Thenanoencapsulation provided TTI protection, gradual release in the desired condition, and improvement of biochemical parameters related to carbohydrate metabolism disorders,without compromising insulinemia.
Assuntos
Glicemia/metabolismo , HDL-Colesterol/sangue , Hiperglicemia/prevenção & controle , Insulina/sangue , Nanopartículas , Tamarindus/química , Inibidores da Tripsina/administração & dosagem , Animais , Quitosana , Preparações de Ação Retardada , Dieta , Jejum , Índice Glicêmico , Hidrólise , Hiperglicemia/sangue , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ratos Wistar , Sementes , Tripsina/metabolismo , Inibidores da Tripsina/farmacologia , Inibidores da Tripsina/uso terapêutico , Proteínas do Soro do LeiteRESUMO
The use of ulinastatin for pancreatitis and sepsis have been described. This study was designed to evaluate the effect of ulinastatin on vascular endothelial cell damage and coagulation in pregnant women with severe pre-eclampsia (PE).From October 2015 to November 2017 at Tianjin Central Hospital of gynecology and obstetrics in China. Eighty pregnant women with severe PE, who elected to deliver by cesarean section, were randomly assigned to a control group or an ulinastatin group. The plasma concentration of von Willebrand factor (vWF) and platelet granule membrane protein (GMP-140), platelet count, fibrinogen levels, prothrombin time (PT), and partial prothrombin activation time (APTT) were recorded before combined spinal-epidural anesthesia and 40 min after administration in both groups.Ulinastatin attenuates vascular endothelial cell damage in pregnant women with PE as indicated by decreased plasma concentrations of vWF and prolonged APTT.
Assuntos
Células Endoteliais/efeitos dos fármacos , Glicoproteínas/farmacologia , Pré-Eclâmpsia/tratamento farmacológico , Inibidores da Tripsina/farmacologia , Adulto , Coagulação Sanguínea/efeitos dos fármacos , Cesárea/efeitos adversos , Feminino , Fibrinogênio/análise , Glicoproteínas/uso terapêutico , Humanos , Selectina-P/sangue , Contagem de Plaquetas , Pré-Eclâmpsia/sangue , Gravidez , Tempo de Protrombina , Valores de Referência , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Inibidores da Tripsina/uso terapêutico , Adulto Jovem , Fator de von Willebrand/análiseRESUMO
OBJECTIVES: Seeds are excellent sources of proteinase inhibitors, some of which may have satietogenic and slimming actions. We evaluated the effect of a trypsin inhibitor from Tamarindus indica L. seeds on weight gain, food consumption and cholecystokinin levels in Wistar rats. METHODS: A trypsin inhibitor from Tamarindus was isolated using ammonium sulfate (30-60%) following precipitation with acetone and was further isolated with Trypsin-Sepharose affinity chromatography. Analyses were conducted to assess the in vivo digestibility, food intake, body weight evolution and cholecystokinin levels in Wistar rats. Histological analyses of organs and biochemical analyses of sera were performed. RESULTS: The trypsin inhibitor from Tamarindus reduced food consumption, thereby reducing weight gain. The in vivo true digestibility was not significantly different between the control and Tamarindus trypsin inhibitor-treated groups. The trypsin inhibitor from Tamarindus did not cause alterations in biochemical parameters or liver, stomach, intestine or pancreas histology. Rats treated with the trypsin inhibitor showed significantly elevated cholecystokinin levels compared with animals receiving casein or water. CONCLUSION: The results indicate that the isolated trypsin inhibitor from Tamarindus reduces weight gain by reducing food consumption, an effect that may be mediated by increased cholecystokinin. Thus, the potential use of this trypsin inhibitor in obesity prevention and/or treatment should be evaluated.
Assuntos
Colecistocinina/sangue , Fitoterapia/métodos , Extratos Vegetais/uso terapêutico , Sementes/química , Tamarindus/química , Inibidores da Tripsina/uso terapêutico , Aumento de Peso/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Digestão/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Trato Gastrointestinal/anatomia & histologia , Masculino , Modelos Animais , Obesidade/tratamento farmacológico , Obesidade/prevenção & controle , Ratos Wistar , Saciação/efeitos dos fármacos , Inibidores da Tripsina/isolamento & purificação , Inibidores da Tripsina/metabolismoRESUMO
OBJECTIVE: The role of Ulinastatin in neuronal injury after cardiopulmonary resuscitation has not been elucidated. We aim to evaluate the effects of Ulinastatin on inflammation, oxidation, and neuronal injury in the cerebral cortex after cardiopulmonary resuscitation. METHODS: Ventricular fibrillation was induced in 76 adult male Wistar rats for 6 min, after which cardiopulmonary resuscitation was initiated. After spontaneous circulation returned, the rats were split into two groups: the Ulinastatin 100,000 unit/kg group or the PBS-treated control group. Blood and cerebral cortex samples were obtained and compared at 2, 4, and 8 h after return of spontaneous circulation. The protein levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were assayed using an enzyme-linked immunosorbent assay, and mRNA levels were quantified via real-time polymerase chain reaction. Myeloperoxidase and Malondialdehyde were measured by spectrophotometry. The translocation of nuclear factor-κB p65 was assayed by Western blot. The viable and apoptotic neurons were detected by Nissl and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). RESULTS: Ulinastatin treatment decreased plasma levels of TNF-α and IL-6, expression of mRNA, and Myeloperoxidase and Malondialdehyde in the cerebral cortex. In addition, Ulinastatin attenuated the translocation of nuclear factor-κB p65 at 2, 4, and 8 hours after the return of spontaneous circulation. Ulinastatin increased the number of living neurons and decreased TUNEL-positive neuron numbers in the cortex at 72 h after the return of spontaneous circulation. CONCLUSIONS: Ulinastatin preserved neuronal survival and inhibited neuron apoptosis after the return of spontaneous circulation in Wistar rats via attenuation of the oxidative stress response and translocation of nuclear factor-κB p65 in the cortex. In addition, Ulinastatin decreased the production of TNF-α, IL-6, Myeloperoxidase, and Malondialdehyde.
Assuntos
Apoptose/efeitos dos fármacos , Reanimação Cardiopulmonar/efeitos adversos , Córtex Cerebral/efeitos dos fármacos , Glicoproteínas/farmacologia , Inibidores da Tripsina/farmacologia , Fibrilação Ventricular/metabolismo , Animais , Western Blotting , Córtex Cerebral/metabolismo , Encefalite/tratamento farmacológico , Glicoproteínas/uso terapêutico , Interleucina-6/sangue , Masculino , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Inibidores da Tripsina/uso terapêutico , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: The role of Ulinastatin in neuronal injury after cardiopulmonary resuscitation has not been elucidated. We aim to evaluate the effects of Ulinastatin on inflammation, oxidation, and neuronal injury in the cerebral cortex after cardiopulmonary resuscitation. METHODS: Ventricular fibrillation was induced in 76 adult male Wistar rats for 6 min, after which cardiopulmonary resuscitation was initiated. After spontaneous circulation returned, the rats were split into two groups: the Ulinastatin 100,000 unit/kg group or the PBS-treated control group. Blood and cerebral cortex samples were obtained and compared at 2, 4, and 8 h after return of spontaneous circulation. The protein levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were assayed using an enzyme-linked immunosorbent assay, and mRNA levels were quantified via real-time polymerase chain reaction. Myeloperoxidase and Malondialdehyde were measured by spectrophotometry. The translocation of nuclear factor-κB p65 was assayed by Western blot. The viable and apoptotic neurons were detected by Nissl and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). RESULTS: Ulinastatin treatment decreased plasma levels of TNF-α and IL-6, expression of mRNA, and Myeloperoxidase and Malondialdehyde in the cerebral cortex. In addition, Ulinastatin attenuated the translocation of nuclear factor-κB p65 at 2, 4, and 8 hours after the return of spontaneous circulation. Ulinastatin increased the number of living neurons and decreased TUNEL-positive neuron numbers in the cortex at 72 h after the return of spontaneous circulation. CONCLUSIONS: Ulinastatin preserved neuronal survival and inhibited neuron apoptosis after the return of spontaneous circulation in Wistar rats via attenuation of the oxidative stress response and translocation of nuclear factor-κB p65 in the cortex. In addition, Ulinastatin decreased the production of TNF-α, ...
Assuntos
Animais , Masculino , Ratos , Apoptose/efeitos dos fármacos , Reanimação Cardiopulmonar/efeitos adversos , Córtex Cerebral/efeitos dos fármacos , Glicoproteínas/farmacologia , Inibidores da Tripsina/farmacologia , Fibrilação Ventricular/metabolismo , Western Blotting , Córtex Cerebral/metabolismo , Encefalite/tratamento farmacológico , Glicoproteínas/uso terapêutico , /sangue , Malondialdeído/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento , Inibidores da Tripsina/uso terapêutico , Fator de Necrose Tumoral alfa/sangueRESUMO
Previous reports have demonstrated increased tryptase-like proteolytic activity in the crevicular fluid of patients with periodontal disease. In the present study, we have investigated the effect of tryptase inhibition with nafamostat mesilate (NM, 6-amino-2-naphtlyl p-guanidinobenzoate dimethansulfonate) on the development of experimental periodontitis in rats. Eighty (80) male Wistar rats were randomly separated into four groups: Control group, NM group (daily 0.1 mg/kg body weight of NM, i.p.), Ligature group (ligature placed at lower right first molars), and NM+Ligature group. The amount of alveolar bone loss (ABL) around the mesial root surface of the first mandibulary molar, as well as the myeloperoxidase (MPO) activity, and total proteolytic activity [N-benzoyl-L: -arginine-p-nitroanilide (BApNA) substrate] were determined at 7 and 14 days. NM led to significantly (p < 0.05) decreased ABL in animals subjected to ligature-induced periodontitis. Tryptase inhibition prevented the onset of significant ABL at 7 days of experiment (0.44 ± 0.16 and 0.60 ± 0.22, p > 0.05, NM+Ligature and Control, respectively) and significantly decreased the ABL at 14 days (0.97 ± 0.17 versus 1.82 ± 0.26, p < 0.001, NM+Ligature versus Ligature, respectively). In addition, NM significantly decreased MPO and total proteolytic activity at 14 days (p < 0.05). These data provided evidence that tryptase inhibition with NM attenuates gingival granulocyte infiltration and ABL in an experimental model of periodontitis in rats.