RESUMO
To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) CONTROL: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: 3 mg/kg bw/day Atorva + BBN. A two phase protocol was used, in which the drug and the carcinogen were given between week 1 and 8 and tumor development or chemoprevention were expressed between week 9 and 20, when the bladders were collected for macroscopic, histological and immunohistochemical (p53, ki67, CD31) evaluation. Serum was assessed for markers of inflammation, proliferation and redox status. The incidence of bladder carcinoma was: control 0/8 (0%); Atorva 0/8 (0%); BBN 13/20 (65%) and Atorva + BBN 1/8 (12.5%). The number and volume of tumors were significantly lower in the Atorva + BBN group, with a marked reduction in hyperplasia, dysplasia and carcinoma in situ lesions. An anti-proliferative, anti-inflammatory and antioxidant profile was also observed in the preventive Atorva group. p53 and ki67 immunostaining were significantly increased in the BBN-treated rats, which was prevented in the Atorva + BBN group. No differences were found for CD31 expression. In conclusion, Atorvastatin had a clear inhibitory effect on bladder cancer development, probably due to its antioxidant, anti-proliferative and anti-inflammatory properties.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticarcinógenos/uso terapêutico , Antioxidantes/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Pirróis/uso terapêutico , Neoplasias da Bexiga Urinária/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Atorvastatina , Biomarcadores Tumorais/sangue , Butilidroxibutilnitrosamina , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ácidos Heptanoicos/farmacologia , Masculino , Estresse Oxidativo , Pirróis/farmacologia , Ratos Wistar , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/metabolismoRESUMO
OBJECTIVE: To investigate the anticarcinogenic effects of sirolimus 2 mg/kg/day on a rat model of urinary bladder carcinogenesis induced with N-butyl-N(4-hydroxybutyl)nitrosamine (BBN). MATERIALS AND METHODS: Thirty-six male Wistar rats were divided into four groups: 1, a control group (eight), given tap water only; 2, a sirolimus control group (eight), given 2 mg/kg/day; 3, a carcinogen (BBN) group (12) exposed to 0.05% BBN; 4, a treatment group (sirolimus/BBN; eight) given 2 mg/kg/day + 0.05% BBN. In the tumour-induction phase, from week 1 to week 8, rats from groups 3 and 4 received BBN ad libitum in drinking water. In the treatment phase, from week 8 to week 20, rats from groups 2 and 4 received sirolimus 2 mg/kg/day by an oesophageal cannula. At week 20 the rats were killed humanely, and the number and size of tumours recorded. The bladders were collected for histological, immunohistochemical and gene expression evaluation. Blood was collected for the determination of several serum proliferative and inflammatory markers. Lipid peroxidation, through serum malondialdehyde (MDA) content, and total antioxidant status (TAS) were also evaluated. RESULTS: Sirolimus caused a marked inhibition of bladder tumour growth. When compared with group 3, group 4 had a reduced proportion of rats with tumour (three of eight vs eight of 12), and significantly fewer tumours per rat, with a mean (sd) of 1.00 (0.0) vs 1.88 (0.35), and tumour volume per tumour, of 0.30 (0.11) vs 66.1 (48.9) mm³, with less aggressive histological changes, i.e. a marked reduction in hyperplasia (four of eight vs 12/12), high-grade dysplasia (four of eight vs 11/12) and urothelial tumour. Rats in group 4 had no infiltrative bladder cancers and had a lower incidence of high-grade tumours than rats in group 3. The rats in group 4 had decreased serum levels of transforming growth factor-ß1, higher levels of tumour necrosis factor-α, and higher levels of serum TAS and a better serum MDA/TAS ratio, a marker of more favourable redox status. Furthermore, the down-regulation of bladder caspase 3 gene expression and the increased Ki67 immunostaining in group 3 were significantly attenuated in group 4. CONCLUSIONS: Sirolimus given as an oral agent, 2 mg/kg/day, significantly inhibited rat bladder carcinogenesis. Sirolimus reduced the number and volume of tumours and induced a less aggressive histological behaviour. This might be due to antiproliferative and antioxidant properties, as well as to the restoration of apoptotic pathways.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Sirolimo/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária , Animais , Butilidroxibutilnitrosamina , Carcinógenos , Caspase 3/metabolismo , Regulação para Baixo , Antígeno Ki-67/metabolismo , Masculino , Ratos , Ratos Wistar , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/patologiaRESUMO
To evaluate the effect of a cyclooxygenase 2 inhibitor, celecoxib (CEL), on bladder cancer inhibition in a rat model, when used as preventive versus as curative treatment. The study comprised 52 male Wistar rats, divided in 5 groups, during a 20-week protocol: control: vehicle, carcinogen: 0.05% of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), CEL: 10 mg/kg/day of the selective COX-2 inhibitor Celebrex, preventive CEL (CEL+BBN-P), and curative CEL (BBN+CEL-C) groups. Although tumor growth was markedly inhibited by the preventive application of CEL, it was even aggravated by the curative treatment. The incidence of gross bladder carcinoma was: control 0/8(0%), BBN 13/20(65%), CEL 0/8(0%), CEL+BBN-P 1/8(12.5%), and BBN+CEL-C 6/8(75%). The number and volume of carcinomas were significantly lower in the CEL+BBN-P versus BBN, accompanied by an ample reduction in hyperplasia, dysplasia, and papillary tumors as well as COX-2 immunostaining. In spite of the reduction of tumor volumes in the curative BBN+CEL-C group, tumor malignancy was augmented. An anti-inflammatory and antioxidant profile was encountered only in the group under preventive treatment. In conclusion, preventive, but not curative, celecoxib treatment promoted a striking inhibitory effect on bladder cancer development, reinforcing the potential role of chemopreventive strategies based on cyclooxygenase 2 inhibition.
Assuntos
Anticarcinógenos/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Neoplasias da Bexiga Urinária/prevenção & controle , Animais , Butilidroxibutilnitrosamina/toxicidade , Celecoxib , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Rim/efeitos dos fármacos , Rim/fisiopatologia , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Masculino , Oxirredução , Ratos , Ratos Wistar , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologiaRESUMO
Adrenal chromaffin cells synthesize and secrete catecholamines and neuropeptides that may regulate hormonal and paracrine signaling in stress and also during inflammation. The aim of our work was to study the role of the cytokine interleukin-1beta (IL-1beta) on catecholamine release and synthesis from primary cell cultures of human adrenal chromaffin cells. The effect of IL-1beta on neuropeptide Y (NPY) release and the intracellular pathways involved in catecholamine release evoked by IL-1beta and NPY were also investigated. We observed that IL-1beta increases the release of NPY, norepinephrine (NE), and epinephrine (EP) from human chromaffin cells. Moreover, the immunoneutralization of released NPY inhibits catecholamine release evoked by IL-1beta. Moreover, IL-1beta regulates catecholamine synthesis as the inhibition of tyrosine hydroxylase decreases IL-1beta-evoked catecholamine release and the cytokine induces tyrosine hydroxylase Ser40 phosphorylation. Moreover, IL-1beta induces catecholamine release by a mitogen-activated protein kinase (MAPK)-dependent mechanism, and by nitric oxide synthase activation. Furthermore, MAPK, protein kinase C (PKC), protein kinase A (PKA), and nitric oxide (NO) production are involved in catecholamine release evoked by NPY. Using human chromaffin cells, our data suggest that IL-1beta, NPY, and nitric oxide (NO) may contribute to a regulatory loop between the immune and the adrenal systems, and this is relevant in pathological conditions such as infection, trauma, stress, or in hypertension.
Assuntos
Glândulas Suprarrenais/citologia , Catecolaminas/metabolismo , Células Cromafins/efeitos dos fármacos , Interleucina-1beta/farmacologia , Neuropeptídeo Y/metabolismo , Óxido Nítrico/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Análise de Variância , Anticorpos/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática/métodos , Expressão Gênica/efeitos dos fármacos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Neuropeptídeo Y/imunologia , Óxido Nítrico/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/antagonistas & inibidoresRESUMO
OBJECTIVE: To evaluate the utility of predicting nonalcoholic fatty liver disease (NAFLD) and obesity by retinal vascular changes (RVC) found in fundoscopy and to determine whether this is related to a low-grade inflammatory process. METHODS: We carried out a cross-sectional analysis that included 152 (ages 18-45 years) patients divided into four groups: NAFLD and BMI less than 25, absence of NAFLD and BMI less than 25, NAFLD and BMI more than 30, and absence of NAFLD and BMI more than 30. Retinal fundoscopy, hepatic ultrasound, metabolic profile, and cytokine measurement were performed. We calculated odds ratio [95% confidence interval (CI)], performed diagnostic utility tests, and carried out a 2 factorial analysis. RESULTS: Obesity was associated with RVC (odds ratio: 21.25; 95% CI: 8.79-51.4) and NAFLD [25 (9.07-72.6)]. NAFLD was associated with RVC [11.24 (4.98-26.48)], and the prediction of NAFLD showed a sensitivity of 75% (95% CI: 68-82) and a specificity of 81% (75-86); when RVC-obesity were combined, sensitivity increased to 90% (88-91.7), with a specificity of 85% (84-85.8). C-reactive protein was associated with the three factors, suggesting an independent contribution. Thin patients with RVC and NAFLD had higher concentrations of interleukin-2, interleukin-6, tumor necrosis factor-α, and interferon-γ. CONCLUSION: NAFLD in patients with obesity without diabetes or hypertension can be predicted by RVC, a noninvasive technique carried out by eye fundoscopy. NAFLD alone can drive inflammatory conditions in the absence of obesity that manifests as RVC.
Assuntos
Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Fotografação , Artéria Retiniana/patologia , Veia Retiniana/patologia , Adolescente , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Citocinas/sangue , Feminino , Humanos , Inflamação/sangue , Inflamação/complicações , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/sangue , Obesidade/diagnóstico , Razão de Chances , Valor Preditivo dos Testes , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: It has become increasingly important to refine therapeutic strategies according to individual patient characteristics. We evaluated the long-term impact of renal function at the time of withdrawing cyclosporine (CsA) in renal allograft recipients receiving sirolimus (SRL), CsA, and steroids (ST). METHODS: At 3 months+/-2 weeks, 430 of 525 patients were eligible to be randomized to remain on triple-therapy (SRL-CsA-ST, n=215) or to have CsA withdrawn (SRL-ST, n=215). Patients were divided into quartiles according to their baseline (last value before randomization) calculated GFR: Assuntos
Ciclosporina/administração & dosagem
, Imunossupressores/administração & dosagem
, Transplante de Rim/imunologia
, Rim/fisiopatologia
, Sirolimo/administração & dosagem
, Doença Aguda
, Adolescente
, Adulto
, Idoso
, Ciclosporina/efeitos adversos
, Ciclosporina/uso terapêutico
, Esquema de Medicação
, Quimioterapia Combinada
, Feminino
, Taxa de Filtração Glomerular
, Rejeição de Enxerto/epidemiologia
, Humanos
, Imunossupressores/efeitos adversos
, Imunossupressores/uso terapêutico
, Incidência
, Transplante de Rim/mortalidade
, Masculino
, Pessoa de Meia-Idade
, Sirolimo/efeitos adversos
, Sirolimo/uso terapêutico
, Esteroides/uso terapêutico
, Resultado do Tratamento
RESUMO
BACKGROUND: This study compared 2-year health-related quality-of-life (HRQL) outcomes of sirolimus (SRL)-treated kidney transplant patients after elimination of cyclosporine A (CsA) to patients continuing on a combined CsA and SRL regimen. METHODS: A randomized, open-label, clinical trial was performed in Europe, Australia, and Canada. Four hundred thirty kidney transplant patients were randomly assigned to sirolimus plus steroids (ST) (n=215) or SRL and CsA+ST (n=215) therapy after 3 months of combined SRL+CsA+ST treatment. HRQL was measured using the Kidney Transplant Questionnaire (KTQ) and the SF-36 Health Survey at month 3 (time of randomization) and months 12 and 24 after transplantation. Repeated-measures analysis of covariance was used to evaluate treatment differences in HRQL scores over the 2-year period. RESULTS: HRQL scores were available for 361 (86%) eligible study patients. Statistically significant treatment-by-assessment time interactions, favoring SRL+ST, were found on KTQ Fatigue (P=0.0158) and Appearance scores (P=0.0007). No treatment differences were observed in KTQ Physical Symptom, Uncertainty-Fear, and Emotion scores. Statistically significant treatment-by-assessment time interactions were observed for SF-36 Vitality scores (P=0.0203) but not other SF-36 scores (P>0.05). For Vitality scores, the SRL+ST group remained stable (mean, 0.4-point change) from month 3 to month 24 compared with decreases in the SRL+CsA+ST group (mean, -6.5-point change). CONCLUSIONS: SRL-based therapy with early elimination of CsA results in fewer appearance-related problems, less fatigue, and better vitality compared with continuous treatment with SRL, CsA, and ST.
Assuntos
Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Qualidade de Vida , Sirolimo/administração & dosagem , Adulto , Análise de Variância , Esquema de Medicação , Quimioterapia Combinada , Emoções/efeitos dos fármacos , Fadiga/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esteroides/administração & dosagem , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: The purpose of this study was to evaluate early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen. METHODS: Within 48 hr after transplantation, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of SRL (troughs >5 ng/mL; immunoassay), CsA, and ST. Those eligible (430) were randomly assigned (1:1) at 3 months +/- 2 weeks to remain on triple-drug therapy (SRL-CsA-ST group) or to have CsA withdrawn and SRL trough concentrations targeted to 20 to 30 ng/mL (SRL-ST group) until month 12, and 15 to 25 ng/mL thereafter. RESULTS: At 24 months, there were no statistically significant differences in patient survival (94.0% vs. 95.3%), graft survival (91.2% vs. 93.5%), acute rejection after randomization (5.1% vs. 9.8%) or discontinuations (34% vs. 33%) for SRL-CsA-ST versus SRL-ST, respectively. Serum creatinine level was significantly better in patients who had CsA withdrawn (167 vs. 128 micromol/L, P<0.001), as was the slope of 1/creatinine. Similarly, systolic blood pressure was lower in patients who had CsA withdrawn (141 vs. 134 mm Hg, P<0.001). High-density lipoprotein cholesterol was significantly higher in the SRL-ST group, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were not significantly different. Hypertension, creatinine increase, abnormal kidney function, toxic nephropathy, edema, hyperuricemia, cataracts, Herpes zoster, and malignancy were reported significantly more often in patients continuing CsA. Thrombocytopenia, hypokalemia, abnormal liver function tests, abnormal wound healing, ileus, and pneumonia were reported significantly more frequently with SRL-ST. CONCLUSION: Data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection.
Assuntos
Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Rim/fisiologia , Sirolimo/administração & dosagem , Pressão Sanguínea , Creatinina/sangue , Ciclosporina/efeitos adversos , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/mortalidade , Sobrevivência de Enxerto/efeitos dos fármacos , Hemoglobinas , Humanos , Imunossupressores/efeitos adversos , Sirolimo/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. METHODS: We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. RESULTS: The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P<0.05] and 70% vs. 47.8% [P<0.05], respectively), whereas no differences were observed in acute lesions (subclinical rejection). Prevalence of CAN at 1 year was lower in this group, as was the severity and incidence of new cases (P<0.05). CONCLUSIONS: Early cyclosporine withdrawal associated with sirolimus administration is followed by an improvement in renal function, a reduction in the progression of chronic pathologic allograft lesions, and a lower incidence of new cases and severity of CAN during the first year after transplantation. This benefit may result in better long-term graft outcome.
Assuntos
Ciclosporina/administração & dosagem , Nefropatias/prevenção & controle , Transplante de Rim/efeitos adversos , Rim/patologia , Sirolimo/uso terapêutico , Adolescente , Adulto , Idoso , Doença Crônica , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
Between May 1990 and October 1998, 67 diabetic patients with end-stage renal disease, on dialysis, were submitted to a standardized protocol in order to assess the coexistence and degree of other diabetic and nondiabetic complications that could affect transplantation. Some of the results were analysed. Type 2 diabetic patients had more abnormal results on the lower limbs doppler ultrasound and on the lower limbs arteriography than type 1 (p < 0.05). Type 2 diabetic patients had more cardiovascular complications so the decision to transplant should be taken on a case by case basis.
Assuntos
Nefropatias Diabéticas/cirurgia , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Transplante de Rim/normas , Masculino , Pessoa de Meia-Idade , Diálise RenalRESUMO
Unclassified sex cord testis tumor is an extremely rare tumor, especially in the adult. It is characterized histologically for a nonspecific combination of testis stromal and epithelial elements, with varying degree of differentiation. Treatment usually consists of radical orchiectomy followed by clinical and imaging surveillance. The available literature about this pathology relies almost exclusively on clinical cases. It's our aim to describe the case of a 37 years old man with an unclassified sex cord testis tumor, the first case described in Portugal, and to review the literature about this issue.
O tumor dos cordões sexuais nÉo classificável do testículo eÌ um tumor extremamente raro, particularmente na idade adulta. Caracteriza-se histologicamente pela conjugaçaÌo inespeciÌfica de elementos estromais e epiteliais do testículo, com grau de diferenciaçÉo variável. A sua abordagem consiste na orquidectomia radical, geralmente realizada antes do diagnóstico, e posterior vigil'ncia clínica e imagioloÌgica. A literatura disponível sobre esta patologia baseia-se quase exclusivamente na descriçÉo de casos clínicos. O nosso objetivo é apresentar o caso de um doente de 37 anos com um tumor dos cordões sexuais nÉo classificável do testículo, o primeiro descrito em Portugal, e fazer uma revisÉo da literatura sobre o tema.
Assuntos
Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Neoplasias Testiculares/patologia , Adulto , Humanos , MasculinoRESUMO
Omega-3 (ω-3) fatty acids have been tested on prevention and treatment of several cancer types, but the efficacy on "in vivo" bladder cancer has not been analyzed yet. This study aimed at evaluating the chemopreventive efficacy of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) mixture in an animal model of bladder cancer. Forty-four male Wistar rats were divided into 4 groups during a 20-week protocol: control; carcinogen-N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN); ω-3 (DHA + EPA); and ω-3 + BBN. BBN and ω-3 were given during the initial 8 weeks. At week 20 blood and bladder were collected and checked for the presence of urothelium lesions and tumors, markers of inflammation, proliferation, and redox status. Incidence of bladder carcinoma was, control (0%), ω-3 (0%), BBN (65%), and ω-3 + BBN (62.5%). The ω-3 + BBN group had no infiltrative tumors or carcinoma in situ, and tumor volume was significantly reduced compared to the BBN (0.9 ± 0.1 mm(3) versus 112.5 ± 6.4 mm(3)). Also, it showed a reduced MDA/TAS ratio and BBN-induced serum CRP, TGF-ß1, and CD31 were prevented. In conclusion, omega-3 fatty acids inhibit the development of premalignant and malignant lesions in a rat model of bladder cancer, which might be due to anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties.
Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/prevenção & controle , Animais , Biomarcadores Tumorais/sangue , Proliferação de Células/efeitos dos fármacos , Quimioprevenção , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/efeitos adversos , Ácidos Graxos Ômega-3/farmacologia , Imuno-Histoquímica , Inflamação/sangue , Inflamação/patologia , Masculino , Oxirredução/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Ratos Wistar , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/patologiaRESUMO
The adrenal gland plays a fundamental role in the response to a variety of stress situations. After a stress condition, adrenal medullary chromaffin cells release, by exocytosis, high quantities of catecholamine (epinephrine, EP; norepinephrine, NE), especially EP. Once in the blood stream, catecholamines reach different target organs, and induce their biological actions through the activation of different adrenoceptors. Adrenal gland cells may also be activated by catecholamines, through hormonal, paracrine and/or autocrine system. The presence of functional adrenoceptors on human adrenal medulla and their involvement on catecholamines secretion was not previously evaluated. In the present study we investigated the role of ß(1)-, ß(2)- and ß(3)-adrenoceptors on catecholamine release from human adrenal chromaffin cells in culture. We observed that the ß-adrenoceptor agonist (isoproterenol) and ß(2)-adrenoceptor agonist (salbutamol) stimulated catecholamine (NE and EP) release from human adrenal chromaffin cells. Furthermore, the ß(2)-adrenoceptor antagonist (ICI 118,551; 100 nM) and ß(3)-adrenoceptor antagonist (SR 59230A; 100 nM) inhibited the catecholamine release stimulated by isoproterenol and nicotine in chromaffin cells. The ß(1)-adrenoceptor antagonist (atenolol; 100 nM) did not change the isoproterenol- neither the nicotine-evoked catecholamine release from human adrenal chromaffin cells. Moreover, our results show that the protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and phospholipase C (PLC) are intracellular mechanisms involved in the catecholamine release evoked by salbutamol. In conclusion, our data suggest that the activation of ß(2)- and ß(3)-adrenoceptors modulate the basal and evoked catecholamine release, NE and EP, via an autocrine positive feedback loop in human adrenal chromaffin cells.
Assuntos
Catecolaminas/metabolismo , Células Cromafins/metabolismo , Receptores Adrenérgicos beta/metabolismo , Sequência de Bases , Células Cultivadas , Primers do DNA , Humanos , Reação em Cadeia da PolimeraseRESUMO
No disponible
Assuntos
Humanos , Feminino , Adulto , Hiperoxalúria Primária/complicações , Transplante de Rim/métodos , Transplante de Fígado/métodos , Resultado do Tratamento , Diálise Renal , Tempo , Oxalatos/urinaRESUMO
Chromaffin cells, sympathetic neurons of the dorsal ganglia, and the intermediate small intensely fluorescent cells derive from a common neural crest progenitor cell. Contrary to the closely related sympathetic nervous system, within the adult adrenal medulla a subpopulation of undifferentiated progenitor cells persists, and recently, we established a method to isolate and differentiate these progenitor cells from adult bovine adrenals. However, no studies have elucidated the existence of adrenal progenitor cells within the human adrenal medulla. Here we describe the isolation, characterization, and differentiation of chromaffin progenitor cells obtained from adult human adrenals. Human chromaffin progenitor cells were cultured in low-attachment conditions for 10-12 days as free-floating spheres in the presence of fibroblast growth factor-2 (FGF-2) and epidermal growth factor. These primary human chromosphere cultures were characterized by the expression of several progenitor markers, including nestin, CD133, Notch1, nerve growth factor receptor, Snai2, Sox9, Sox10, Phox2b, and Ascl1 on the molecular level and of Sox9 on the immunohistochemical level. In opposition, phenylethanolamine N-methyltransferase (PNMT), a marker for differentiated chromaffin cells, significantly decreased after 12 days in culture. Moreover, when plated on poly-l-lysine/laminin-coated slides in the presence of FGF-2, human chromaffin progenitor cells were able to differentiate into two distinct neuron-like cell types, tyrosine hydroxylase (TH)(+)/ß-3-tubulin(+) cells and TH(-)/ß-3-tubulin(+) cells, and into chromaffin cells (TH(+)/PNMT(+)). This study demonstrates the presence of progenitor cells in the human adrenal medulla and reveals their potential use in regenerative medicine, especially in the treatment of neuroendocrine and neurodegenerative diseases.
Assuntos
Medula Suprarrenal/citologia , Diferenciação Celular , Proliferação de Células , Células Cromafins/metabolismo , Células-Tronco/citologia , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Fator de Crescimento Epidérmico/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Proteínas de Filamentos Intermediários/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nestina , RNA/análise , Tubulina (Proteína)/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
No disponible
Assuntos
Humanos , Masculino , Idoso , Dermatomiosite/diagnóstico , Transplante de Rim , Insuficiência Renal Crônica , Rim Policístico Autossômico Recessivo/complicações , Doenças Autoimunes , Imunossupressores/uso terapêutico , Hospedeiro ImunocomprometidoRESUMO
PURPOSE: To evaluate the efficacy of a selective cyclooxygenase-2 (COX-2) inhibitor in rat bladder cancer chemoprevention, as well as to assess the relevance of inflammation, proliferation and oxidative stress in tumor growth and in its prevention. RESULTS: The main findings were: (I) the incidence of carcinoma was: control: 0% (0/8); BBN: 65% (13/20); CEL: 0% (0/8) and BBN + CEL: 12.5% (1/8); (II) the mean tumor volume per rat with tumor and per tumor were significantly lower in the BBN + CEL group (21.2 and 5.3 +/- 0.4 mm(3)) vs. BBN (138.5 +/- 7.5 and 112.5 +/- 6.4 mm(3)); (III) the incidence of pre-neoplasic (hyperplasia and dysplasia) and neoplasic (papillary tumors and carcinoma in situ-CIS) lesions were notoriously reduced in the CEL + BBN treatment; (IV) CEL significantly reduced serum TGFbeta1 and CRP and increase TNFalpha and IL-1beta (p < 0.001); (V) CEL reduced MDA formation in serum (p < 0.001) and liver (p < 0.05) and also showed a trend to reduction in kidney. METHODS: Drug treatments were performed during the first 8 w, followed by 12 w for tumor expression/prevention, in the following groups: control-vehicle; carcinogen-0.05% of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN); celecoxib (CEL)-10 mg/kg/day and preventive CEL + BBN. The bladders were analyzed for number and volume of tumor and nature of urothelium lesions. Serum was assessed for markers of inflammation, proliferation and redox status. CONCLUSIONS: Celecoxib has demonstrated an outstanding inhibitory effect on bladder cancer chemoprevention, which might be due to its expected anti-inflammatory actions, as well as by anti-proliferatory and antioxidant actions. This data supports a pivotal role of cancer chemoprevention strategies based on COX-2 inhibition.