RESUMO
Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli bacteraemia can induce unfavourable clinical outcomes due to delay in appropriate antimicrobial treatment and limited therapeutic options. Therefore, elucidating the predictors of ESBL-producing E. coli-induced bacteraemia is crucial to improve clinical outcomes. However, a literature search did not reveal any studies that incorporate a meta-analysis of the predictors of ESBL-producing E. coli-induced bacteraemia. As such, this review was undertaken to assess current evidence on the predictors of ESBL-producing E. coli-induced bacteraemia. PubMed, Web of Science and Cochrane Library databases were searched for all relevant publications from January 2000 to September 2021. This systematic review evaluated 10 observational studies, comprising a total of 2325 patients with E. coli-induced bacteraemia and 850 (36.6%) ESBL-producing strains. In the meta-analysis, previous antibiotic therapy [pooled risk ratio (RR) 2.72; P<0.001], especially with cephalosporins (pooled RR 4.66; P<0.001) and quinolones (pooled RR 5.47; P<0.001), and urinary catheter use (pooled RR 3.79; P<0.001) were predictive of ESBL-producing E. coli-induced bacteraemia. Antibiotic therapy for patients with the above-mentioned risk factors should be selected considering the possibility of ESBL-producing E. coli-induced bacteraemia compared with non-ESBL-producing E. coli-induced bacteraemia. It is important to elucidate whether appropriate modulation of the identified risk factors can potentially mitigate the risk of ESBL-producing E. coli-induced bacteraemia compared with non-ESBL-producing E. coli-induced bacteraemia.
Assuntos
Bacteriemia , Infecções por Escherichia coli , Humanos , Escherichia coli , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/tratamento farmacológico , beta-Lactamases , Fatores de Risco , Antibacterianos/uso terapêutico , Bacteriemia/epidemiologia , Bacteriemia/tratamento farmacológicoRESUMO
BACKGROUND: Exhaled nitric oxide (FeNO) associates with asthma and eosinophilic inflammation. However, relationships between nitric oxide synthases, arginase, FeNO, asthma severity and inflammation remain poorly understood. OBJECTIVES: To determine the relationships of iNOS expression/activation and arginase 2 expression with asthma severity, FeNO, nitrotyrosine (NT) and eosinophilic inflammation. METHODS: Bronchial brushings and sputum were obtained from 25 normal controls, eight mild/no inhaled corticosteroids (ICS), 16 mild-moderate/with ICS and 35 severe asthmatics. The FeNO was measured the same day by ATS/ERS standards. The iNOS, arginase2 mRNA/protein and NT protein were measured in lysates from bronchial brushings by quantitative real-time PCR and Western blot. Induced sputum differentials were obtained. RESULTS: Severe asthma was associated with the highest levels of iNOS protein and mRNA, although the index of iNOS mRNA to arginase2 mRNA most strongly differentiated severe from milder asthma. When evaluating NO-related enzyme functionality, iNOS mRNA/protein expression both strongly predicted FeNO (r = 0.61, P < 0.0001 for both). Only iNOS protein predicted NT levels (r = 0.48, P = 0.003) with the strongest relationship in severe asthma (r = 0.61, P = 0.009). The iNOS protein, FeNO and NT, all correlated with sputum eosinophils, but the relationships were again strongest in severe asthma. Controlling for arginase 2 mRNA/protein did not impact any functional outcome. CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that while iNOS expression from epithelial brushings is highest in severe asthma, factors controlling arginase2 mRNA expression significantly improve differentiation of severity. In contrast, functionality of the NO pathway as measured by FeNO, NT and eosinophilic inflammation, is strongly associated with iNOS expression alone, particularly in severe asthma.
Assuntos
Asma/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo , Adulto , Arginase/genética , Arginase/metabolismo , Asma/diagnóstico , Asma/imunologia , Ativação Enzimática , Eosinófilos/imunologia , Expiração , Feminino , Expressão Gênica , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Active cigarette smoking has detrimental effects on asthma morbidity and severity. Angiopoietin-1 has been shown to protect the microvessels against plasma leakage, whereas angiopoietin-2 enhances vascular permeability and subsequently induces airway mucosal oedema. Therefore, it is recently thought that angiopoietin-2 may contribute to the pathophysiology of asthma. OBJECTIVE: To determine whether angiopoietin-2 levels in the airways are associated with clinical profiles in smoking asthmatics. METHODS: We measured angiopoietin-1 and -2 levels in induced sputum in 35 normal controls (18 non-smokers and 17 smokers) and 49 asthmatics (24 non-smokers and 25 smokers) before and after inhaled beclomethasone dipropionate (BDP: 800 microg/day) therapy for 12 weeks. RESULTS: Angiopoietin-1 and -2 levels in induced sputum were significantly higher in asthmatics than in normal controls. Moreover, angiopoietin-2 levels were significantly higher in smoking asthmatics than in non-smoking asthmatics (P=0.0001). The airway vascular permeability index was also higher in smoking asthmatics than in non-smoking asthmatics. Moreover, the angiopoietin-2 level was positively correlated with the airway vascular permeability index (non-smoking asthmatics: r=0.87, P<0.001, smoking asthmatics: r=0.64, P=0.002). After BDP therapy, angiopoietin-1 levels were significantly decreased in non-smoking asthmatics, smoking-cessation asthmatics, and active-smoking asthmatics. In contrast, angiopoietin-2 levels did not differ from before to after BDP therapy in non-smoking asthmatics and active-smoking asthmatics. However, its levels were significantly decreased from before to after BDP therapy in smoking-cessation asthmatics (P=0.002). Although forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) before BDP therapy was comparable in all subgroups, this parameter after BDP therapy was significantly lower in active-smoking asthmatics than in non-smoking and smoking-cessation asthmatics. Moreover, the reduction in angiopoietin-2 levels after BDP therapy in smoking-cessation asthmatics was significantly correlated with an improvement in FEV(1)/FVC. CONCLUSION: Angiopoietin-2 levels were elevated in the airways of smoking asthmatics, and its levels were associated with impaired airway responses.
Assuntos
Angiopoietina-2/metabolismo , Asma/metabolismo , Fumar/metabolismo , Escarro/metabolismo , Adulto , Angiopoietina-1/análise , Angiopoietina-1/metabolismo , Angiopoietina-2/análise , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Asma/fisiopatologia , Beclometasona/administração & dosagem , Permeabilidade Capilar/efeitos dos fármacos , Edema/tratamento farmacológico , Edema/metabolismo , Edema/fisiopatologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Mucosa Respiratória/metabolismo , Mucosa Respiratória/fisiopatologia , Fumar/fisiopatologia , Abandono do Hábito de FumarRESUMO
Bronchial asthma and allergic rhinitis frequently coexist. This study investigated correlations of health-related quality of life (QOL) questionnaires for these diseases, assessing whether the selective leukotriene receptor antagonist (LTRA), pranlukast, had additional benefits to overall asthma control when there was concomitant allergic rhinitis. Patients with asthma-associated allergic rhinitis were randomly allocated to either LTRA(+) (n = 21, treated for 3 months with pranlukast), or LTRA(-) (n = 8, no pranlukast). At study start and at 3 months, pulmonary function was evaluated and QOL assessments were made using the Asthma Health Questionnaire-Japan (AHQ-Japan) and the Japan Rhino-conjunctivitis Quality of Life Questionnaire (JRQLQ). Total scores were significantly correlated both before and after therapy. After 3 months' therapy, pulmonary function and total AHQ-Japan and JRQLQ scores significantly improved in the LTRA(+) group, but not in the LTRA(-) group. A significant correlation between change at 3 months in the AHQ-Japan and JRQLQ scores from baseline values was seen in the LTRA(+) group. LTRA therapy improved allergic rhinitis symptoms, asthma symptoms and pulmonary function.
Assuntos
Asma/complicações , Asma/tratamento farmacológico , Antagonistas de Leucotrienos/uso terapêutico , Qualidade de Vida , Rinite Alérgica Perene/complicações , Rinite Alérgica Perene/tratamento farmacológico , Inquéritos e Questionários , Asma/fisiopatologia , Cromonas/uso terapêutico , Feminino , Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Rinite Alérgica Perene/fisiopatologiaRESUMO
Galectins constitute a family of proteins that bind to beta-galactoside residues and have diverse physiological functions. Here we report on the identification of a galectin-like molecule, galectin-12, in a human adipose tissue cDNA library. The protein contained two potential carbohydrate-recognition domains with the second carbohydrate-recognition domain being less conserved compared with other galectins. In vitro translated galectin-12 bound to a lactosyl-agarose column far less efficiently than galectin-8. Galectin-12 mRNA was predominantly expressed in adipose tissue of human and mouse and in differentiated 3T3-L1 adipocytes. Caloric restriction and treatment of obese animals with troglitazone increased galectin-12 mRNA levels and decreased the average size of the cells in adipose tissue. The induction of galectin-12 expression by the thiazolidinedione, troglitazone, was paralleled by an increase in the number of apoptotic cells in adipose tissue. Immunocytochemical analysis revealed that galectin-12 was localized in the nucleus of adipocytes, and transfection with galectin-12 cDNA induced apoptosis of COS-1 cells. These results suggest that galectin-12, an adipose-expressed galectin-like molecule, may participate in the apoptosis of adipocytes.
Assuntos
Apoptose , Proteínas de Ciclo Celular/química , Hemaglutininas/química , Lectinas/química , Tiazolidinedionas , Células 3T3 , Adipócitos/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Northern Blotting , Células COS , Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , DNA Complementar/metabolismo , Galactosídeos/metabolismo , Galectinas , Biblioteca Gênica , Humanos , Imuno-Histoquímica , Lectinas/metabolismo , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Ligação Proteica , Biossíntese de Proteínas , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Ratos , Ratos Zucker , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Tiazóis/farmacologia , Distribuição Tecidual , TransfecçãoRESUMO
Betacellulin (BTC), a member of the epidermal growth factor family, is expressed predominantly in the human pancreas and induces the differentiation of a pancreatic acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC has a physiologically important role in the endocrine pancreas. In this study, we examined the in vivo effect of recombinant human BTC (rhBTC) on glucose intolerance and pancreatic morphology using a new mouse model with glucose intolerance induced by selective alloxan perfusion. RhBTC (1 microg/g body wt) or saline was injected subcutaneously every day from the day after alloxan treatment. The intraperitoneal glucose tolerance test revealed no difference between rhBTC-treated and rhBTC-untreated glucose-intolerant mice at 2-4 weeks. However, glucose tolerance was significantly improved and body weight was significantly increased in rhBTC-treated mice compared with untreated mice at 8 weeks. Islet-like cell clusters, consisting mainly of beta-cells, were increased in the pancreas and were localized in contact with the ductal lining cells and sometimes with acinar cells. In conclusion, administration of rhBTC improved glucose tolerance in this mouse model by increasing beta-cell volume, primarily through accelerated neogenesis from ductal lining cells.
Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Intolerância à Glucose/fisiopatologia , Substâncias de Crescimento/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular , Ilhotas Pancreáticas/efeitos dos fármacos , Animais , Betacelulina , Peso Corporal , Divisão Celular/efeitos dos fármacos , Teste de Tolerância a Glucose , Substâncias de Crescimento/sangue , Humanos , Imuno-Histoquímica/métodos , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pâncreas/metabolismo , Pâncreas/patologia , Proteínas Recombinantes , Coloração e Rotulagem , Fatores de TempoRESUMO
Adipose tissue is a major site of glycerol production in response to energy balance. However, molecular basis of glycerol release from adipocytes has not yet been elucidated. We recently cloned a novel member of the aquaporin family, aquaporin adipose (AQPap), which has glycerol permeability. The current study was designed to examine the hypothesis that AQPap serves as a glycerol channel in adipocytes. Adipose tissue expressed AQPap mRNA in high abundance, but not the mRNAs for the other aquaglyceroporins, AQP3 and AQP9, indicating that AQPap is the only known aquaglyceroporin expressed in adipose tissue. Glycerol release from 3T3-L1 cells was increased during differentiation in parallel with AQPap mRNA levels and suppressed by mercury ion, which inhibits the function of AQPs, supporting AQPap functions as a glycerol channel in adipocytes. Fasting increased and refeeding suppressed adipose AQPap mRNA levels in accordance with plasma glycerol levels and oppositely to plasma insulin levels in mice. Insulin dose-dependently suppressed AQPap mRNA expression in 3T3-L1 cells. AQPap mRNA levels and adipose glycerol concentrations measured by the microdialysis technique were increased in obese mice with insulin resistance. Accordingly, negative regulation of AQPap expression by insulin was impaired in the insulin-resistant state. Exposure of epinephrine translocated AQPap protein from perinuclear cytoplasm to the plasma membrane in 3T3-L1 adipocytes. These results strongly suggest that AQPap plays an important role in glycerol release from adipocytes.
Assuntos
Tecido Adiposo/metabolismo , Aquaporinas/metabolismo , Glicerol/metabolismo , Canais Iônicos/metabolismo , Células 3T3 , Animais , Aquaporinas/genética , Transporte Biológico , Proteínas de Transporte , Epinefrina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerol/sangue , Imuno-Histoquímica , Insulina/farmacologia , Cloreto de Mercúrio/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Dados de Sequência Molecular , Perilipina-1 , Fosfoproteínas/genética , RNA Mensageiro/metabolismo , Esterol Esterase/genéticaRESUMO
N-Oxidation of benzydamine (BZY) mediated by flavin-containing monooxygenase (FMO) was evaluated by microdialysis in vivo in different regions of rat brain and liver. The probe was implanted into local regions of the brain, such as the olfactory bulb, cerebral cortex, corpus striatum, hippocampus and cerebellum, or the hepatic lobe. By perfusing BZY via the probe, BZY N-oxide was identified in the dialysate. The estimated concentrations of BZY N-oxide in extracellular fluid were almost the same as those in the olfactory bulb, hippocampus and cerebral cortex, half the concentration in the hepatic lobe; however, the concentration in the corpus striatum was lower and that in the cerebellum was higher than in the other regions. These results demonstrate that the extracellular concentration of BZY N-oxide formed in vivo was unexpectedly high in every brain region.
Assuntos
Benzidamina/metabolismo , Encéfalo/metabolismo , Fígado/metabolismo , Oxigenases/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/ultraestrutura , Espaço Extracelular/metabolismo , Técnicas In Vitro , Fígado/enzimologia , Fígado/ultraestrutura , Masculino , Microdiálise , Microssomos/metabolismo , Oxirredução , Ratos , Ratos WistarRESUMO
Benzydamine (BZY) N-oxidation mediated by flavin-containing monooxygenase (FMO) was evaluated in perfused brain and liver. Following 20 min of perfusion with modified Ringer solution, the infusion of BZY into brain or liver led to production of BZY N-oxide. BZY N-oxide, a metabolite of BZY oxidized exclusively by FMO, was mostly recovered in the effluent without undergoing further metabolism or reduction back to the parent substrate. The BZY N-oxide formation rate increased as the infusion concentration of BZY increased both in perfused brain and perfused liver. BZY N-oxidation activities in perfused rat brain and liver were 4.2 nmol/g brain/min and 50 nmol/g liver/min, respectively, although the BZY N-oxidation activity in brain homogenates was one 4000th that in liver homogenates. This is the first study of FMO activity in brain in situ.
Assuntos
Benzidamina/metabolismo , Encéfalo/enzimologia , Fígado/enzimologia , Oxigenases/metabolismo , Animais , Benzidamina/análogos & derivados , Técnicas In Vitro , Cinética , Masculino , Microssomos/enzimologia , Microssomos Hepáticos/enzimologia , Oxirredução , Perfusão , Ratos , Ratos Wistar , Distribuição TecidualRESUMO
To clarify the regeneration process of pancreatic beta-cells, we established a new mouse model of diabetes induced by selective perfusion of alloxan after clamping the superior mesenteric artery. In this model, diabetes could be induced by the destruction of beta-cells in alloxan-perfused segments, while beta-cells in nonperfused segments were spared. Intraperitoneal glucose tolerance tests showed glucose intolerance, which gradually ameliorated and was completely normalized in 1 year with a concomitant increase of insulin content in the pancreas. Histological examination showed neo-islet formation in the alloxan-perfused segment and the proliferation of spared beta-cells in the nonperfused segment. In the alloxan-perfused segment, despite a marked reduction of islets in size and number at an early stage, both the number of islets, including islet-like cell clusters (ICCs), and the relative islet area significantly increased at a later stage. Increased single beta-cells and ICCs were located in close contact with duct cell lining, suggesting that they differentiated from duct cells and that such extra-islet precursor cells may be important for beta-cell regeneration in beta-cell-depleted segment. In addition to beta-cells, some nonhormone cells in ICCs were positive for nuclear insulin promoter factor 1, which indicated that most, if not all, nonhormone cells positive for this factor were beta-cell precursors. In the nonperfused segment, the islet area increased significantly, and the highest 5-bromo-2-deoxyuridine-labeling index in beta-cells was observed at day 5, while the number of islets did not increase significantly. This indicated that the regeneration of islet endocrine cells occurs mostly through the proliferation of preexisting intra-islet beta-cells in the nonperfused segment. In conclusion, the regeneration process of beta-cells varied by circumstance. Our mouse model is useful for studying the mechanism of regeneration, since differentiation and proliferation could be analyzed separately in one pancreas.
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Proteínas de Homeodomínio , Ilhotas Pancreáticas/fisiologia , Regeneração/fisiologia , Aloxano , Animais , Glicemia/análise , Glicemia/metabolismo , Peso Corporal/fisiologia , Divisão Celular/fisiologia , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Glucagon/análise , Glucagon/imunologia , Teste de Tolerância a Glucose , Imuno-Histoquímica , Insulina/análise , Insulina/imunologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/ultraestrutura , Queratinas/análise , Queratinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Polipeptídeo Pancreático/análise , Polipeptídeo Pancreático/imunologia , Perfusão , Somatostatina/análise , Somatostatina/imunologia , Fatores de Tempo , Transativadores/análise , Transativadores/imunologiaRESUMO
The cerebral resistance to hypoxia in mice was investigated by measuring the survival time under both hypobaric and normobaric hypoxic conditions. In the ad libitum fed mice, there was a circadian variation in the survival time that was longer during the light period than during the dark period under hypobaric hypoxic conditions. The survival time under normobaric hypoxic conditions also exhibited a similar circadian variation in the ad libitum fed mice, whereas the rhythm of the survival time was completely reversed by the restriction of food presentation (9:00-15:00). These findings suggest that there is a circadian rhythm in the cerebral resistance of mice to hypoxia, which can be shifted by the time of food presentation. Furthermore, regression analyses revealed a negative correlation between the survival time of mice exposed to hypoxia and body temperature, and blood glucose levels. These indicate that the cerebral resistance to hypoxia was intimately associated with body temperature and blood glucose that both show a circadian rhythm in mice.
Assuntos
Encéfalo/fisiopatologia , Ritmo Circadiano/fisiologia , Hipóxia/fisiopatologia , Animais , Glicemia/análise , Temperatura Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Análise de RegressãoRESUMO
The circadian variation of decapitation-induced gasping was investigated by measuring the gasping duration of isolated mouse head after decapitation under both normal and restricted feeding conditions. In the normally fed mice, there was a circadian periodicity in the gasping duration: it was longer during the light period than during the dark period. The circadian periodicity was completely reversed by the restriction of food. The circadian periodicity of the gasping duration were conversely parallel to those of body temperature in both normal and feeding restricted mice, and regression analysis revealed a negative correlation between the gasping duration and body temperature. Furthermore, pentobarbital and ethanol, agents that caused hypothermia, markedly prolonged the gasping duration. These findings suggest that there is a circadian periodicity in the brain reactivity after complete ischemia, which may be associated with the changes of body temperature.
Assuntos
Isquemia Encefálica/fisiopatologia , Ritmo Circadiano/fisiologia , Mecânica Respiratória/fisiologia , Animais , Temperatura Corporal/fisiologia , Morte Encefálica/fisiopatologia , Etanol/farmacologia , Hipotermia Induzida , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pentobarbital/farmacologia , Fatores de TempoRESUMO
The anti-hypoxic effect (assessed by a standard hypoxia survival test) 3 hr after 2-cyclohexene-1-one (CHX) was completely abolished by injections of L-cysteine after CHX. Under these conditions, brain GSH was depleted to about 50% of the control level in CHX-treated mice and recovered to about 80% of control level following L-cysteine post-treatment. However, D-cysteine could not cause such effects. Intracerebroventricular injection of CHX, which caused a selective depletion of brain GSH, produced an anti-hypoxic effect. Thus, the anti-hypoxic effect may be related to the decrease of brain GSH levels.
Assuntos
Química Encefálica/efeitos dos fármacos , Cicloexanos/farmacologia , Cicloexanonas/farmacologia , Glutationa/deficiência , Hipóxia/tratamento farmacológico , Cetonas/farmacologia , Animais , Cicloexanonas/efeitos adversos , Cicloexanonas/uso terapêutico , Cisteína/farmacologia , Injeções Intraventriculares , Cetonas/efeitos adversos , Cetonas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , EstereoisomerismoRESUMO
2-Cyclohexene-1-one (CHX) dose-dependently caused the elevation of blood glucose levels in both fed and fasted mice. Adrenalectomy considerably prevented the elevated blood glucose with CHX, and plasma adrenaline assays revealed about a three- to fifteen-fold rise after CHX treatment. These findings indicate that the CHX-induced hyperglycemia may be largely mediated by adrenaline released from the adrenal medulla.
Assuntos
Cicloexanos/farmacologia , Cicloexanonas/farmacologia , Hiperglicemia/induzido quimicamente , Adrenalectomia , Animais , Glicemia/metabolismo , Corticosterona/farmacologia , Epinefrina/sangue , Epinefrina/farmacologia , Hiperglicemia/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICRRESUMO
The effect of various reduced glutathione (GSH) depletors on the survival time under normobaric and hypobaric hypoxia was examined in mice. The survival time was markedly prolonged in mice treated with glutathione S-transferase substrate, 2-cyclohexene-1-one (50-100 mg/kg, ip) and phorone (100-250 mg/kg, ip). The anti-hypoxic effect lasted for at least 3 hr and the maximum effect was found 0.5 hr after injection. Further, both compounds significantly elevated blood glucose levels 0.5-1 hr after treatment. The extent of the elevated blood glucose was nearly comparable to that of the mice treated with glucose (1-2 g/kg, ip), which was found to possess an anti-hypoxic effect. However, a GSH synthesis inhibitor, buthionine sulfoximine, could cause neither a prolongation of survival time of hypoxic mice nor an elevation of blood glucose. Moreover, unlike the depletion of hepatic GSH, brain GSH was markedly decreased by 2-cyclohexene-1-one and phorone, but not by buthionine sulfoximine. These findings suggest that the elevated blood glucose may involve in one of the mechanisms of the anti-hypoxic effect of 2-cyclohexene-1-one and phorone. A relationship between the anti-hypoxic effect and the depletion of brain GSH was also discussed.
Assuntos
Cicloexanos/farmacologia , Cicloexanonas/farmacologia , Glutationa/metabolismo , Hipóxia/fisiopatologia , Cetonas/farmacologia , Metionina Sulfoximina/análogos & derivados , Animais , Glicemia/análise , Encéfalo/metabolismo , Butionina Sulfoximina , Hipóxia/metabolismo , Fígado/metabolismo , Masculino , Metionina Sulfoximina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Compostos de Sulfidrila/metabolismoRESUMO
To search for a technique to deplete reduced glutathione (GSH) in brain, the influence of various types of compounds on brain GSH levels was investigated in mice. Of the compounds tested, cyclohexene-1-one, cycloheptene-1-one and diethyl maleate were shown to be potent GSH depletors in brain as well as in liver. The depletion of cerebral GSH ranged about 40-60% of control levels at 1 and 3 hr after intraperitoneal injection. Cyclohexene, cycloheptene, phorone, acetaminophen, and benzyl chloride caused mild depletion of cerebral GSH, but buthionine sulfoximine did not alter cerebral GSH levels. Further, intracerebroventricular injection of cyclohexene-1-one and cycloheptene-1-one caused depletion of brain GSH to about 60-80% of control levels at 1 hr after injection, and the effects persisted for at least 6 hr. Under these conditions, hepatic GSH was not altered. These results demonstrated that cyclohexene-1-one and cycloheptene-1-one can cause not only a marked depletion of brain GSH by systemic administration, but also depletion of cerebral GSH by intracerebroventricular injection by virtue of being water-soluble compounds. Thus, methods for depleting brain GSH employing both compounds are available for exploring possible functions of cerebral GSH in in vivo systems.
Assuntos
Encéfalo/metabolismo , Glutationa/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Cicloeptanos/administração & dosagem , Cicloeptanos/farmacologia , Cicloexanonas/administração & dosagem , Cicloexanonas/farmacologia , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Cetonas/farmacologia , Cinética , Masculino , Maleatos/farmacologia , Camundongos , Camundongos Endogâmicos ICRRESUMO
Human and animal studies were performed to investigate the causes of diabetic autonomic neuropathy. Human diabetics, with and without autonomic neuropathy, were measured for plasma catecholamine response to insulin hypoglycemia and for urinary catecholamine excretion. In streptozotocin-diabetic rats, plasma catecholamine response and tissue catecholamine concentrations were measured at various stages of the disease. As the duration of the diabetic state lengthens in rats, there is a time-proportional stepwise decrease in plasma catecholamine response. This is similar to the clinical course observed in human diabetics, which also includes a reduction of catecholamine excretion after the appearance of autonomic neuropathy. After 6 weeks of diabetes, rat tissue is found to have an increased concentration of catecholamines; this may represent a compensatory reaction to the difficulties of secretion. At 13 weeks of diabetes, tissue catecholamine concentrations return to almost normal, when plasma responses have disappeared. These results suggest that the impaired secretion of catecholamines in diabetics may be a cause of diabetic autonomic neuropathy.
Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Neuropatias Diabéticas/etiologia , Epinefrina/urina , Norepinefrina/urina , Animais , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Catecolaminas/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Humanos , Hipotensão Ortostática , Insulina/uso terapêutico , Norepinefrina/sangue , RatosRESUMO
Administration of poly(ADP-ribose) synthetase inhibitors such as nicotinamide to 90% depancreatized rats induces regeneration of pancreatic islets, thereby ameliorating the surgical diabetes (Yonemura, Y., Takashima, T., Miwa, K., Miyazaki, I., Yamamoto, H., and Okamoto, H. (1984) Diabetes 33, 401-404). In screening the regenerating islet-derived cDNA library, we came across a novel gene encoding a 165-amino acid protein. The gene was expressed in regenerating islets but not in normal pancreatic islets, insulinomas, or regenerating liver. In 90% depancreatized and nicotinamide-injected rats, the expression of the gene was increased 1 month after the partial pancreatectomy and reached a peak 3 months after the operation. The increase in expression of the gene was temporally correlated with the increase in size of regenerating islets and the decrease in urinary glucose level. The gene was also found to be activated in hyperplastic islets of aurothioglucose-treated mice. Thus, the expression of the gene in both regenerating and hyperplastic islets suggests possible roles for this gene in replication, growth, and maturation of islet beta-cells. We also found that a human pancreas-derived cDNA library contained a homologue to the gene.
Assuntos
Regulação da Expressão Gênica , Genes , Ilhotas Pancreáticas/fisiologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Humanos , Masculino , Dados de Sequência Molecular , Niacinamida/farmacologia , Pancreatectomia , Inibidores de Poli(ADP-Ribose) Polimerases , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos , Regeneração/efeitos dos fármacosRESUMO
The disulfiram-like effect of various beta-lactam antibiotics containing N-methyltetrazolethiol (NMTT) on the alcohol-metabolizing system was studied using rats. Their administration caused decreased activities in low Km aldehyde dehydrogenase (ALDH) and acetaldehyde oxidation in the liver, with marked depression from several hours to 2 days after the treatment. Blood acetaldehyde level increased markedly when ethanol was administered 18-24 hr after pretreatment with antibiotics. A similar time course change in the effect was obtained when disulfiram was administered. The following results obtained in the present study indicate that the disulfiram-like effect associated with these antibiotics was not mediated by the whole molecular structures of these drugs: Firstly, the antibiotics were eliminated rapidly from the plasma and liver, and the disulfiram-like effect was followed by a disappearance of the drugs. Secondly, the concentration of antibiotics required to inhibit mitochondrial low Km ALDH activity in vitro was very high compared with their liver concentration. Thirdly, rapid onset of disulfiram-like effects occurred after administration of NMTT itself, and a pronounced elevation of blood acetaldehyde level was observed when ethanol was administered 3-5 hr after the NMTT injection. Fourthly, almost the same amounts of NMTT were released in the body after the intravenous administration of various NMTT-containing antibiotics, as judged by the urinary excretion. These results suggest that the disulfiram-like effect of beta-lactam antibiotics is mediated by NMTT released from them.
Assuntos
Álcoois/metabolismo , Antibacterianos/farmacologia , Azóis/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Tetrazóis/farmacologia , Acetaldeído/sangue , Aldeído Desidrogenase/metabolismo , Animais , Antibacterianos/urina , Cefamandol/farmacologia , Etanol/sangue , Antagonistas dos Receptores Histamínicos H1/urina , Fígado/enzimologia , Masculino , Mitocôndrias Hepáticas/enzimologia , Moxalactam/farmacologia , Ratos , Ratos Endogâmicos , Frações Subcelulares/enzimologia , Tetrazóis/urina , Fatores de TempoRESUMO
Age and sex dependent differences of N-acetyl-beta-D-glucosaminidase (NAG) and L-alanine aminopeptidase (AAP) activities in kidney, urine and plasma of male and female mice were studied. The sex difference in NAG activity appeared between 27 and 38 days of age with the manifestation of significant differences in body weight and kidney growth. NAG activity in male kidneys was 3-fold that in females and its urinary level in mature males was over 10-fold higher. Androgenic regulation was found not only in the NAG contents in the kidneys and in the urinary excretion but also in the plasma NAG level, which showed higher in females. On the other hand, AAP activity in kidney, urine and plasma did not show much sex differences. Age related changes in AAP activity were not found except in the kidney and marked androgenic regulation was also not found in AAP. These results indicate that NAG and AAP, which are both urinary enzymes used as indicators of renal lesions, may be regulated differently.