RESUMO
BACKGROUND AND AIMS: Pancreatic resection is associated with pancreatic exocrine insufficiency (PEI) leading to nutritional consequences. The Pancreatic Nutrition Clinic was established to diagnose and manage PEI through standardised nutritional assessment. In this prospective observational study, we aimed to define the rate of PEI, diabetes mellitus and nutritional abnormalities in patients who underwent pancreatic resection. METHODS: All Pancreatic Nutrition Clinic patients were included for analysis. Clinical data were prospectively obtained at initial assessment. Biochemical data included micronutrient levels, faecal elastase-1 and haemoglobin A1c. Bone mineral density and nutritional assessment were undertaken. RESULTS: Ninety-eight patients were included. Fifty-nine per cent (58/98) had undergone a pancreatoduodenectomy. Ninety-three patients had a faecal elastase-1 result, 65% (60/93) of which had a faecal elastase-1 less than 200 µg/g of faeces. Seventy-five patients (76%) of the total population required PERT, and thirty-nine (40%) were classified as malnourished using the patient-generated subjective global assessment tool. Seventy-two per cent (70/97) had a biochemical deficiency of one or more micronutrients. Thirty-eight people (39%) had diabetes mellitus. Of the seventy-eight patients with a bone mineral density scan available for analysis, 29% (23/78) had osteoporosis and 49% (38/78) osteopenia. CONCLUSIONS: Pancreatic exocrine insufficiency, micronutrient deficiency, bone disease, diabetes mellitus and malnutrition are highly prevalent in patients who have undergone pancreatic resection.
Assuntos
Diabetes Mellitus , Insuficiência Pancreática Exócrina , Desnutrição , Doenças Metabólicas , Humanos , Insuficiência Pancreática Exócrina/diagnóstico , Elastase Pancreática/análise , MicronutrientesRESUMO
We undertook a systematic review and meta-analysis of published papers assessing dietary protein and bone health. We found little benefit of increasing protein intake for bone health in healthy adults but no indication of any detrimental effect, at least within the protein intakes of the populations studied. This systematic review and meta-analysis analysed the relationship between dietary protein and bone health across the life-course. The PubMed database was searched for all relevant human studies from the 1st January 1976 to 22nd January 2016, including all bone outcomes except calcium metabolism. The searches identified 127 papers for inclusion, including 74 correlational studies, 23 fracture or osteoporosis risk studies and 30 supplementation trials. Protein intake accounted for 0-4% of areal BMC and areal BMD variance in adults and 0-14% of areal BMC variance in children and adolescents. However, when confounder adjusted (5 studies) adult lumbar spine and femoral neck BMD associations were not statistically significant. There was no association between protein intake and relative risk (RR) of osteoporotic fractures for total (RR(random) = 0.94; 0.72 to 1.23, I2 = 32%), animal (RR (random) = 0.98; 0.76 to 1.27, I2 = 46%) or vegetable protein (RR (fixed) = 0.97 (0.89 to 1.09, I2 = 15%). In total protein supplementation studies, pooled effect sizes were not statistically significant for LSBMD (total n = 255, MD(fixed) = 0.04 g/cm2 (0.00 to 0.08, P = 0.07), I2 = 0%) or FNBMD (total n = 435, MD(random) = 0.01 g/cm2 (-0.03 to 0.05, P = 0.59), I2 = 68%). There appears to be little benefit of increasing protein intake for bone health in healthy adults but there is also clearly no indication of any detrimental effect, at least within the protein intakes of the populations studied (around 0.8-1.3 g/Kg/day). More studies are urgently required on the association between protein intake and bone health in children and adolescents.
Assuntos
Densidade Óssea/efeitos dos fármacos , Proteínas Alimentares/farmacologia , Envelhecimento/fisiologia , Densidade Óssea/fisiologia , Dieta/estatística & dados numéricos , Proteínas Alimentares/administração & dosagem , Humanos , Proteínas do Leite/administração & dosagem , Proteínas do Leite/farmacologia , Fraturas por Osteoporose/etiologia , Fraturas por Osteoporose/fisiopatologia , Fraturas por Osteoporose/prevenção & controle , Medição de Risco/métodos , Proteínas de Soja/administração & dosagem , Proteínas de Soja/farmacologiaRESUMO
A summary of systematic reviews and meta-analyses addressing the benefits and risks of dietary protein intakes for bone health in adults suggests that dietary protein levels even above the current RDA may be beneficial in reducing bone loss and hip fracture risk, provided calcium intakes are adequate. Several systematic reviews and meta-analyses have addressed the benefits and risks of dietary protein intakes for bone health in adults. This narrative review of the literature summarizes and synthesizes recent systematic reviews and meta-analyses and highlights key messages. Adequate supplies of dietary protein are required for optimal bone growth and maintenance of healthy bone. Variation in protein intakes within the "normal" range accounts for 2-4% of BMD variance in adults. In older people with osteoporosis, higher protein intake (≥ 0.8-g/kg body weight/day, i.e., above the current RDA) is associated with higher BMD, a slower rate of bone loss, and reduced risk of hip fracture, provided that dietary calcium intakes are adequate. Intervention with dietary protein supplements attenuate age-related BMD decrease and reduce bone turnover marker levels, together with an increase in IGF-I and a decrease in PTH. There is no evidence that diet-derived acid load is deleterious for bone health. Thus, insufficient dietary protein intakes may be a more severe problem than protein excess in the elderly. Long-term, well-controlled randomized trials are required to further assess the influence of dietary protein intakes on fracture risk.
Assuntos
Proteínas Alimentares/administração & dosagem , Osteoporose/prevenção & controle , Equilíbrio Ácido-Base/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Cálcio da Dieta/administração & dosagem , Proteínas Alimentares/efeitos adversos , Proteínas Alimentares/farmacologia , Humanos , Fraturas por Osteoporose/prevenção & controle , Medição de Risco/métodosRESUMO
We recently demonstrated that a novel storage and transport mechanism for nitric oxide (NO) mediated by glutathione-S-transferase P1 (GSTP1) and multidrug resistance protein 1 (MRP1/ABCC1), protects M1-macrophage (M1-MØ) models from large quantities of endogenous NO. This system stores and transports NO as dinitrosyl-dithiol-iron complexes (DNICs) composed of iron, NO and glutathione (GSH). Hence, this gas with contrasting anti- and pro-tumor effects, which has been assumed to be freely diffusible, is a tightly-regulated species in M1-MØs. These control systems prevent NO cytotoxicity and may be responsible for delivering cytotoxic NO as DNICs via MRP1 from M1-MØs, to tumor cell targets.
Assuntos
Glutationa S-Transferase pi/metabolismo , Células Matadoras Naturais/metabolismo , Macrófagos/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Óxido Nítrico/metabolismo , Substâncias Protetoras/metabolismo , Glutationa/metabolismo , HumanosRESUMO
Iron is a crucial transition metal for virtually all life. Two major destinations of iron within mammalian cells are the cytosolic iron-storage protein, ferritin, and mitochondria. In mitochondria, iron is utilized in critical anabolic pathways, including: iron-storage in mitochondrial ferritin, heme synthesis, and iron-sulfur cluster (ISC) biogenesis. Although the pathways involved in ISC synthesis in the mitochondria and cytosol have begun to be characterized, many crucial details remain unknown. In this review, we discuss major aspects of the journey of iron from its initial cellular uptake, its modes of trafficking within cells, to an overview of its downstream utilization in the cytoplasm and within mitochondria. The understanding of mitochondrial iron processing and its communication with other organelles/subcellular locations, such as the cytosol, has been elucidated by the analysis of certain diseases e.g., Friedreich's ataxia. Increased knowledge of the molecules and their mechanisms of action in iron processing pathways (e.g., ISC biogenesis) will shape the investigation of iron metabolism in human health and disease.
Assuntos
Células/metabolismo , Doença , Ferro/metabolismo , Animais , Transporte Biológico , Humanos , Proteínas Ferro-Enxofre/metabolismo , Mitocôndrias/metabolismo , Modelos BiológicosAssuntos
Colite/virologia , Infecções por Citomegalovirus/complicações , Citomegalovirus , Hematemese/virologia , Melena/virologia , Infecções por Citomegalovirus/virologia , Hemorragia Gastrointestinal/virologia , Transplante de Coração , Humanos , Terapia de Imunossupressão/efeitos adversos , Masculino , Ilustração Médica , Pessoa de Meia-Idade , Complicações Pós-Operatórias/virologiaRESUMO
Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and its analogues are potent anti-cancer agents through their ability to target lysosomes. Considering this, it was important to understand the mechanisms involved in the Dp44mT-mediated induction of autophagy and the role of 5'-adenosine monophosphate-activated protein kinase (AMPK) as a critical autophagic regulator. As such, this investigation examined AMPK's role in the regulation of the transcription factor EB (TFEB), which transcribes genes involved in autophagy and lysosome biosynthesis. For the first time, this study demonstrated that Dp44mT induces translocation of TFEB to the nucleus. Furthermore, Dp44mT-mediated nuclear translocation of TFEB was AMPK-dependent. Considering that: (1) the mammalian target of rapamycin complex 1 (mTORC1) plays an important role in the regulation of TFEB; and (2) that AMPK is a known regulator of mTORC1, this study also elucidated the mechanisms through which Dp44mT regulates nuclear translocation of TFEB via AMPK. Silencing AMPK led to increased mTOR phosphorylation, that activates mTORC1. Since Dp44mT inhibits mTORC1 in an AMPK-dependent manner through raptor phosphorylation, Dp44mT is demonstrated to regulate TFEB translocation through dual mechanisms: AMPK activation, which inhibits mTOR, and inhibition of mTORC1 via phosphorylation of raptor. Collectively, Dp44mT-mediated activation of AMPK plays a crucial role in lysosomal biogenesis and TFEB function. As Dp44mT potently chelates copper and iron that are crucial for tumor growth, these studies provide insight into the regulatory mechanisms involved in intracellular clearance and energy metabolism that occur upon alterations in metal ion homeostasis.
Assuntos
Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Antineoplásicos/farmacologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Núcleo Celular/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Tiossemicarbazonas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/química , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Relação Estrutura-Atividade , Tiossemicarbazonas/química , Células Tumorais CultivadasRESUMO
Upon activation, the 5'-adenosine monophosphate-activated protein kinase (AMPK) increases catabolism, while inhibiting anabolism. The anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), activates AMPK in multiple tumor cell-types (Biochim. Biophys Acta 2016;1863:2916-2933). This acts as an initial cell "rescue response" after iron-depletion mediated by Dp44mT. Considering Dp44mT-mediated AMPK activation, the role of AMPK on Dp44mT cytotoxicity was examined. Dp44mT increased the p-AMPK/AMPK ratio in multiple tumor cell-types over short (24 h) and longer (72 h) incubations. Notably, Dp44mT was more effective in inhibiting tumor cell proliferation after AMPK silencing, potentially due to the loss of AMPK-mediated metabolic plasticity that protects cells against Dp44mT cytotoxicity. The silencing of AMPK-increased cellular cholesterol and stabilized lysosomes against Dp44mT-mediated lysosomal membrane permeabilization. This was substantiated by studies demonstrating that the cholesterol-depleting agent, methyl-ß-cyclodextrin (MßCD), restores Dp44mT-mediated lysosomal membrane permeabilization in AMPK silenced cells. The increased levels of cholesterol after AMPK silencing were independent of the ability of AMPK to inhibit the rate-limiting step of cholesterol synthesis via the inactivating phosphorylation of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) at Ser872. In fact, Dp44mT did not increase phosphorylation of HMGCR at (Ser872), but decreased total HMGCR expression similarly in both the presence or absence of AMPK silencing. Dp44mT was demonstrated to increase autophagic initiation after AMPK silencing via an AMPK- and Beclin-1-independent mechanism. Further, there was increased cleaved caspase 3 and cleaved PARP after incubation of AMPK silenced cells with Dp44mT. Overall, AMPK silencing promotes Dp44mT anti-proliferative activity, suggesting a role for AMPK in rescuing its cytotoxicity by inhibiting autophagy and also apoptosis.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Tiossemicarbazonas/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Fosforilação/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Tiossemicarbazonas/uso terapêuticoRESUMO
UNLABELLED: Vitamin C may play a role in bone health. In the Framingham Study, subjects with higher total or supplemental vitamin C intake had fewer hip fractures and non-vertebral fractures as compared to subjects with lower intakes. Therefore, vitamin C may have a protective effect on bone health in older adults. INTRODUCTION: Dietary antioxidants such as vitamin C may play a role in bone health. We evaluated associations of vitamin C intake (total, dietary, and supplemental) with incident hip fracture and non-vertebral osteoporotic fracture, over a 15- to 17-year follow-up, in the Framingham Osteoporosis Study. METHODS: Three hundred and sixty-six men and 592 women (mean age 75 +/- 5 years) completed a food frequency questionnaire (FFQ) in 1988-1989 and were followed for non-vertebral fracture until 2003 and hip fracture until 2005. Tertiles of vitamin C intake were created from estimates obtained using the Willett FFQ, after adjusting for total energy (residual method). Hazard ratios were estimated using Cox-proportional hazards regression, adjusting for covariates. RESULTS: Over follow-up 100 hip fractures occurred. Subjects in the highest tertile of total vitamin C intake had significantly fewer hip fractures (P trend = 0.04) and non-vertebral fractures (P trend = 0.05) compared to subjects in the lowest tertile of intake. Subjects in the highest category of supplemental vitamin C intake had significantly fewer hip fractures (P trend = 0.02) and non-vertebral fractures (P trend = 0.07) compared to non-supplement users. Dietary vitamin C intake was not associated with fracture risk (all P > 0.22). CONCLUSION: These results suggest a possible protective effect of vitamin C on bone health in older adults.
Assuntos
Ácido Ascórbico/administração & dosagem , Suplementos Nutricionais , Fraturas do Quadril/prevenção & controle , Fraturas por Osteoporose/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Densidade Óssea/efeitos dos fármacos , Fatores de Confusão Epidemiológicos , Dieta/estatística & dados numéricos , Métodos Epidemiológicos , Feminino , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/etiologia , Humanos , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Osteoporose/complicações , Osteoporose/epidemiologia , Osteoporose/prevenção & controle , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Potássio na Dieta/administração & dosagemRESUMO
The metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), is a stress response protein that is involved in the inhibition of multiple oncogenic signaling pathways. Initial studies have linked NDRG1 and the endoplasmic reticulum (ER) stress response. Considering this, we extensively examined the mechanism by which NDRG1 regulates the ER stress response in pancreatic and colon cancer cells. We also examined the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which induces NDRG1 expression and causes ER stress. The expression of NDRG1 was demonstrated to regulate the three main arms of the ER stress response by: (1) increasing the expression of three major ER chaperones, binding immunoglobulin protein (BiP), calreticulin, and calnexin; (2) suppressing the protein kinase, RNA-activated (PKR)-like ER kinase (PERK); (3) inhibiting the inositol-requiring kinase 1α (IRE1α) arm; and (4) increasing the cleavage of activating transcription factor 6 (ATF6). An important finding was that NDRG1 enhances the anti-proliferative and anti-migratory activity of Dp44mT. This increased efficacy could be related to the following effects in the presence of Dp44mT and NDRG1, namely: markedly increased activation of the PERK target, eukaryotic translation initiation factor 2α (eIF2α); the maintenance of activating transcription factor 4 (ATF4) expression; high cytosolic Ca+2 that increases the sensitivity of cells to apoptosis via activation of the calmodulin-dependent kinase II (CaMKII) signaling cascade; and increased pro-apoptotic C/EBP-homologous protein (CHOP) expression. Collectively, this investigation dissects the molecular mechanisms through which NDRG1 manipulates the ER stress response and its ability to potentiate the activity of the potent anti-cancer agent, Dp44mT.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fator 6 Ativador da Transcrição/antagonistas & inibidores , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calnexina/genética , Calnexina/metabolismo , Calreticulina/genética , Calreticulina/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/antagonistas & inibidores , Endorribonucleases/genética , Endorribonucleases/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Quelantes de Ferro/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismoRESUMO
BACKGROUND: Fibroblast growth factor (FGF)-2 is a critical growth factor in normal and malignant cell proliferation and tumor-associated angiogenesis. Fibrinogen and fibrin bind to FGF-2 and modulate FGF-2 functions. Furthermore, we have shown that extrahepatic epithelial cells are capable of endogenous production of fibrinogen. OBJECTIVE: Herein we examined the role of fibrinogen and FGF-2 interactions on prostate and lung adenocarcinoma cell growth in vitro. METHODS: Cell proliferation was measured by (3)H-thymidine uptake and the specificity of FGF-2-fibrinogen interactions was measured using wild-type and mutant FGF-2s, fibrinogen gamma-chain (FGG) RNAi and co-immunoprecipitation. Metabolic labeling, immunopurification and fluorography demonstrated de novo fibrinogen production. RESULTS: FGF-2 stimulated DU-145 cell proliferation, whereas neither FGF-2 nor fibrinogen affected the growth of PC-3 or A549 cells. Fibrinogen augmented the proliferative effect of FGF-2 on DU-145 cells. The role of fibrinogen in FGF-2-enhanced DNA synthesis was confirmed using an FGF-2 mutant that exhibits no binding affinity for fibrinogen. FGG transcripts were present in PC-3, A549 and DU-145 cells, but only PC-3 and A549 cells produced detectable levels of intact protein. RNAi-mediated knockdown of FGG expression resulted in decreased production of fibrinogen protein and inhibited (3)H-thymidine uptake in A549 and PC-3 cells by 60%, which was restored by exogenously added fibrinogen. FGF-2 and fibrinogen secreted by the cells were present in the medium as a soluble complex, as determined by coimmunoprecipitation studies. CONCLUSIONS: These data indicate that endogenously synthesized fibrinogen promotes the growth of lung and prostate cancer cells through interaction with FGF-2.
Assuntos
Fibrinogênio/biossíntese , Fator 2 de Crescimento de Fibroblastos/farmacologia , Neoplasias/metabolismo , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Fibrinogênio/genética , Fibrinogênio/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Neoplasias/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/farmacologia , Células Tumorais CultivadasRESUMO
The influence of purified porcine relaxin on contractility of human cervical smooth muscle was investigated in vitro. Strips of cervical tissue were obtained by needle biopsy from pregnant and nonpregnant women and were mounted in a superfused organ chamber for isometric measurement of contractile activity. Relaxin (0.005-25 micrograms/ml) inhibited the spontaneous contractions in cervical strips from 18% of nonpregnant, 68% of early pregnant, and in 100% of term pregnant women. These results indicate that relaxin has an inhibitory action on cervical smooth muscle and that this effect is more constantly detected as pregnancy proceeds.
Assuntos
Colo do Útero/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Relaxina/farmacologia , Animais , Feminino , Idade Gestacional , Humanos , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Gravidez , SuínosRESUMO
Endothelial cell responses at sites of injury occur in a fibrin matrix and are regulated by growth factors including those of the FGF and VEGF families. The pericellular proteolytic balance is important in these responses, and FGF-2 and VEGF up-regulate endothelial cell u-PA, u-PAR and PAI-1. Because both VEGF and FGF-2 bind to fibrinogen, we have examined the capacity of fibrinogen to modulate the up-regulation of these proteins by FGF-2 and VEGF. Confluent cultures of endothelial cells were exposed to FGF-2, VEGF, and fibrinogen or to combinations of growth factors with fibrinogen. Changes in mRNA levels of u-PA, u-PAR and PAI-1 were measured by Northern blot. FGF-2 increased u-PA, u-PAR, and PAI-1 mRNA, but there was a significantly greater induction when fibrinogen was added to FGF-2 at all concentrations. The potentiation by fibrinogen was particularly evident at an FGF-2 concentration of 0.1 ng mL(-1), which resulted in non-significant change in transcript levels by itself, but significantly increased up to 2.6-fold with fibrinogen. VEGF also increased endothelial cell expression of u-PA, u-PAR and PAI-1, but this effect was not potentiated by fibrinogen. Addition of LM609, a monoclonal antibody to alphaVbeta3, significantly inhibited induction of u-PA mRNA and activity by fibrinogen-bound FGF-2 compared to FGF-2. A monoclonal antibody to FGFR1 also inhibited u-PA mRNA expression induced by fibrinogen-bound FGF-2. We conclude that fibrinogen increases the capacity of FGF-2, but not of VEGF, to up-regulate u-PA, u-PAR, and PAI-1 in endothelial cells and that fibrinogen-bound FGF-2 requires alphaVbeta3 binding to up-regulate endothelial cell u-PA.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Fibrinogênio/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Inibidor 1 de Ativador de Plasminogênio/genética , Receptores de Superfície Celular/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Fator A de Crescimento do Endotélio Vascular/farmacologia , Sequência de Bases , Células Cultivadas , DNA Complementar/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Proteínas Recombinantes/farmacologiaRESUMO
Hexokinase, phosphofructokinase and pyruvate kinase, the regulatory enzymes of the glycolytic sequence, showed progressive increases in their activities with the rise of parasitaemia in Plasmodium knowlesi-infected rhesus monkey serum and red blood cells. Chloroquine therapy cleared the parasitaemia in 72 h and brought the elevated levels of these enzymes back to almost normal in about 30 days.
Assuntos
Cloroquina/uso terapêutico , Hexoquinase/sangue , Malária/enzimologia , Fosfofrutoquinase-1/sangue , Piruvato Quinase/sangue , Animais , Macaca mulatta , Malária/tratamento farmacológico , Plasmodium knowlesiRESUMO
The effects of adrenoceptor agonists and antagonists on the contractile activity of cervical strips from early pregnant and nonpregnant women were studied. Noradrenaline and the alpha-adrenoceptor agonist, phenylephrine, had a stimulatory effect on smooth muscle activity. This response could be blocked totally by the alpha-adrenoceptor antagonist, phenoxybenzamine. Isoprenaline, known to be a beta-adrenoceptor agonist with some alpha-adrenoceptor activity, had stimulatory and inhibitory effects, whereas the beta 2-adrenoceptor agonist, terbutaline, exhibited a pure inhibitory action. The inhibitory effects of isoprenaline and terbutaline were totally blocked by the beta-adrenoceptor antagonist propranolol. In pregnant patients, the sensitivity to noradrenaline was significantly higher, and the inhibitory action of terbutaline was less pronounced, which indicated the predominance of alpha-receptor activity in the uterine cervix during pregnancy.
Assuntos
Colo do Útero/inervação , Receptores Adrenérgicos/fisiologia , Contração Uterina/efeitos dos fármacos , Adolescente , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Colo do Útero/efeitos dos fármacos , Colo do Útero/fisiologia , Feminino , Humanos , Técnicas In Vitro , Pessoa de Meia-Idade , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Gravidez , Receptores Adrenérgicos/efeitos dos fármacosRESUMO
The contractile activity of smooth muscle from the pregnant and nonpregnant human cervix uteri was studied in organ bath experiments. Several patterns of spontaneous activity with varying frequency and amplitude were observed. Prostaglandin E2 inhibited muscle activity in a concentration-dependent manner, and total inhibition was achieved in pregnant tissue at extremely low concentrations. Prostaglandin F2 alpha, on the other hand, did not influence spontaneous contractions. Prostaglandin I2 and 6-keto-prostaglandin F1 alpha had an inhibitory effect but only at comparatively high concentrations. 5,8,11,14-Eicosatetraynoic acid and indomethacin abolished spontaneous contractions, indicating a regulatory influence of endogenous prostanoids on cervical contractility. The extreme sensitivity to prostaglandin E2 and enhancement of its action during early pregnancy provide evidence for a specific role of this compound in controlling cervical smooth muscle activity in the human female.
Assuntos
Colo do Útero/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Prostaglandinas/farmacologia , Contração Uterina/efeitos dos fármacos , 6-Cetoprostaglandina F1 alfa/farmacologia , Adolescente , Adulto , Dinoprosta , Dinoprostona , Feminino , Humanos , Técnicas In Vitro , Pessoa de Meia-Idade , Gravidez , Prostaglandinas E/farmacologia , Prostaglandinas F/farmacologiaRESUMO
Amperometric glucose sensors were constructed based on solid graphite electrodes, surface-modified with NAD+ dependent glucose dehydrogenase (GDH), Toluidine Blue O (TBO), and protective ionic polymers. The electrocatalytic oxidation of NADH was evaluated from cyclic voltammetry with TBO dissolved, adsorbed, and electrostatically or covalently bound to polymers. The NADH and glucose sensors constructed were investigated and operated at 0 mV vs. Ag/AgCl using single potential step chronoamperometry. The operational stability of the glucose sensors was limited by leakage of NAD+. A glucose sensitivity much higher than carbon paste electrode was found. A sensitivity as high as 25 microA cm-2 mM-1 was achieved.
Assuntos
Técnicas Biossensoriais , Glucose Desidrogenase , Glucose/análise , NAD/análise , Cloreto de Tolônio , Enzimas Imobilizadas , Glucose 1-Desidrogenase , OxirreduçãoRESUMO
In order to examine whether cocaine-induced behavioral sensitization is modulated by changes in serotonin receptor subtypes, we measured the binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) to 5-HT1A receptors and of [3H]-ketanserin to 5-HT2 receptors in various brain regions of cocaine-treated and saline-treated (control) rats. As previously reported, repeated administration of cocaine resulted in behavioral sensitization. Stereotypic scores with the cocaine challenge were significantly (P < 0.05) higher in cocaine-pretreated animals than in the saline-pretreated group. Neither acute nor chronic cocaine administration significantly altered the number (Bmax) or the affinity (KD) of either [3H]8-OH-DPAT or [3H]ketanserin binding sites in any of the brain regions examined. These results suggest that the enhanced functional sensitivity of 5-HT1A or 5-HT2 receptor subtypes seen with cocaine may be associated with alterations in processes distal to receptors rather than changes in the number or the affinity of the receptors.