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Background and study aims: The gastrointestinal (GI) tract is the most common site of extra-nodal involvement for non-Hodgkin's lymphoma (NHL). The features of GI NHLs remain unclear. The aim of this study was to clarify endoscopic characteristics of GI NHLs. Patients and methods: We retrospectively analyzed the morphological characteristics of 63 GI malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma. Lesions were diagnosed between 2005 and 2020. Macroscopic findings were classified into five subtypes: superficial (S); protruding without ulcer (P); protruding with ulcer (PU); fungating (F); and multiple nodules (MN). Results: Thirty-one lesions in the stomach were classified as S type in 3 cases (9.6%), P type in 6 (19%), PU type in 13 (42%), and F type in 9 (29%). In the stomach, the ulcerated phenotype was more frequent for diffuse large B-cell lymphoma (DLBCL) (89.5%) than for other histological types (41.7%; P = 0.01). In the intestine, 23 tumors were classified as S type in 4 cases (17%), P type in 1 (4%), PU type in 6 (26%), F type in 1 (4%), and MN in 11 (48%). Eleven of the 14 cases (78.6%) of intestinal follicular lymphoma lesions showed MN type. In the colon, eight tumors were classified as S type in 2 cases (25%), P type in 2 (25%), PU type in 1 (13%), and F type in 3 (38%). Conclusion: We have clarified the endoscopic features of GI NHL using macroscopic classifications. The ulcerated phenotype was the most frequent endoscopic finding for DLBCL.
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Neoplasias Gastrointestinais , Linfoma de Zona Marginal Tipo Células B , Linfoma Difuso de Grandes Células B , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/patologia , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Estudos Retrospectivos , ÚlceraRESUMO
Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has been successfully used to treat some patients with colorectal cancer and those with head and neck squamous cell carcinoma (HNSCC). For the effective treatment, it is essential to first identify cetuximab-responsive patients. The level of EGFR expression and/or the presence of mutations in signalling molecules downstream of the EGFR pathway have been reported to be determining factors for cetuximab responsiveness in colorectal cancer patients; however, limited data have been reported for HNSCC patients. We previously reported that the chemokine CXCL14 exhibits tumour-suppressive effects against xenografted HNSCC cells, which may be classified into two groups, CXCL14-expressing and non-expressing cells under serum-starved culture conditions. Here we employed CXCL14-expressing HSC-3 cells and CXCL14-non-expressing YCU-H891 cells as representatives of the two groups and compared their responses to cetuximab and their CXCL14 expression under various conditions. The growth of xenografted tumours initiated by HSC-3 cells, which expressed CXCL14 in vivo and in vitro, was suppressed by the injection of cetuximab into tumour-bearing mice; however, neither the expression of the chemokine nor the cetuximab-dependent suppression of xenograft tumour growth was observed for YCU-H891 cells. Both types of cells expressed EGFR and neither type harboured mutations in signalling molecules downstream of EGFR that have been reported in cetuximab-resistant colon cancer patients. The inhibition of the extracellular signal-regulated kinase (ERK) signalling increased the levels of CXCL14 messenger RNA (mRNA) in HSC-3 cells, but not in YCU-H891 cells. We also observed that the CXCL14 promoter region in YCU-H891 cells was hypermethylated, and that demethylation of the promoter by treatment with 5-aza-2'-deoxycytidine restored CXCL14 mRNA expression and in vivo cetuximab-mediated tumour growth suppression. Finally, we observed in vivo tumour growth suppression when YCU-H891 cells were engineered to express CXCL14 ectopically in the presence of doxycycline. These results indicate that CXCL14 expression may be a good predictive biomarker for cetuximab-dependent tumour suppression.
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The objective of this work was to evaluate the effect of adding different starches (native and modified) on the physicochemical, sensory, structural and microbiological characteristics of low-fat chicken mortadella. Two formulations containing native cassava and regular corn starch, coded CASS (5.0 % of cassava starch) and CORN (5.0 % of regular corn starch), and one formulation produced with physically treated starch coded as MOD1 (2.5 % of Novation 2300) and chemically modified starch coded as MOD2 (2.5 % of Thermtex) were studied. The following tests were performed: physicochemical characterization (moisture, ash, protein, starch and lipid contents, and water activity); cooling, freezing and reheating losses; texture (texture profile test); color coordinates (L*, a*, b*, C and h); microbiological evaluation; sensory evaluation (multiple comparison and preference test); and histological evaluation (light microscopy). There was no significant difference (p > 0.05) for ash, protein, cooling loss, cohesiveness or in the preference test for the tested samples. The other evaluated parameters showed significant differences (p < 0.05). Histological study allowed for a qualitative evaluation between the physical properties of the food and its microscopic structure. The best results were obtained for formulation MOD2 (2.5 % Thermtex). The addition of modified starch resulted in a better performance than the native starch in relation to the evaluated technological parameters, mainly in relation to reheating losses, which demonstrated the good interaction between the modified starch in the structure of the product and the possibility of the application of this type of starch in other types of functional meat products.
Assuntos
Maxila/patologia , Neoplasias do Seio Maxilar/diagnóstico , Líquido da Lavagem Nasal/citologia , Neoplasias de Células Escamosas/diagnóstico , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Núcleo Celular/patologia , Gengiva/diagnóstico por imagem , Humanos , Imuno-Histoquímica , Masculino , Invasividade Neoplásica/diagnóstico , Radiografia , Extração Dentária/métodosRESUMO
In this 12-week, randomized, double-blind, placebo-controlled trial, the efficacy and safety of transglucosidase (TGD) were compared with placebo in patients with type 2 diabetes mellitus (T2DM). At 12 weeks, TGD 300 mg/day and TGD 900 mg/day significantly reduced HbA1c (0.18 and 0.21%) and insulin concentration (19.4 and 25.0 pmol/l), respectively, vs. placebo. TGD 300 mg/day and TGD 900 mg/day also significantly reduced low-density lipoprotein cholesterol (0.22 and 0.17 mmol/l, respectively). TGD 900 mg/day significantly reduced triglyceride by 0.24 mmol/l and diastolic blood pressure by 8 mmHg. Placebo was associated with a significant increase from baseline in body mass index, alanine aminotransferase and aspartate aminotransferase (0.17 kg/m(2) , 3 and 2 U/l, respectively), whereas TGD was not. TGD 300 mg/day significantly increased high-molecular-weight adiponectin by 0.6 µg/ml. Adverse events did not differ significantly between the groups. TGD resulted in lowering of HbA1c and blood insulin level and improvements in metabolic and cardiovascular risk factors in T2DM.
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Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosiltransferases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Adiponectina/sangue , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/sangue , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangueRESUMO
Beta-tricalcium phosphate (ß-TCP) is widely used in clinical orthopedic surgery due to its high biodegradability, osteoconductivity, easy manipulation and lack of histotoxicity. However, little is known about the molecular mechanisms responsible for the beneficial effects of ß-TCP in bone formation. In this study, ß-TCP was implanted in dog mandibles, after which the gene expression profiles and signaling pathways were monitored using microarray and Ingenuity Pathways Analysis (IPA). Following the extraction of premolars and subsequent bone healing, ß-TCP was implanted into the artificial osseous defect. Histological evaluation (H-E staining) was carried out 4, 7 and 14 days after implantation. In addition, total RNA was isolated from bone tissues and gene expression profiles were examined using microarray analysis coupled with Ingenuity Pathways Analysis (IPA). Finally, real-time PCR was used to confirm mRNA levels. It was found that ß-TCP implantation led to a two-fold change in 3409 genes on day 4, 3956 genes on day 7, and 6899 genes on day 14. Among them, the expression of collagen type I α1 (COL1A1), alkaline phosphatase (ALP) and transforming growth factor (TGF)-ß2 was increased on day 4, the expression of receptor activator of NF-kappaB ligand (RANKL) and interferon-γ (IFN-γ) was decreased on day 7, and the expression of osteoprotegerin (OPG) was decreased on day 14, affecting the bone morphogenetic protein (BMP), Wnt/ß-catenin and nuclear factor-kappaB (NF-κB) signaling pathways in osteoblasts and osteoclasts. Simultaneously, vascular cell adhension molecule (VCAM)-1 expression was increased on day 4 and stromal cell-derived factor (SDF)-1 expression was increased on days 4 and 14. Taken together, these findings shed light on some of the cellular events associated with bone formation, bioresorption, regeneration and healing of ß-TCP following its implantation. The results suggest that ß-TCP enhances bone healing processes and stimulates the coordinated actions of osteoblasts and osteoclasts, leading to bone regeneration.
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Fosfatos de Cálcio/metabolismo , Perfilação da Expressão Gênica , Mandíbula/metabolismo , Animais , Cães , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de SinaisRESUMO
BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RT-PCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/genética , Idoso , Linhagem Celular Tumoral , Ciclina D2 , Ciclinas/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/patologia , Supressão GenéticaRESUMO
BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) has recently gained popularity for use against intramucosal gastric neoplasms in Japan, but few studies have examined whether ESD is feasible for elderly patients. This study aims are to evaluate the efficacy and safety of ESD according to age in consecutive elderly patients treated with ESD. PATIENTS AND METHODS: Subjects comprised 116 patients (90 men, 26 women) with 125 lesions treated using ESD from November 2002 to March 2006 at Nagoya City University Hospital and Iwata Municipal Hospital, Japan. Patients were categorized into: Group A, <65-years-old (n=34); Group B, > or =65-years-old but <75-years-old (n=41); and Group C, > or = 75-years-old (n=41). En bloc resection rate and treatment time were examined according to age, tumour size and location, and frequency of complications was examined according to age. RESULTS: Rate of concomitant disease was significantly higher in Group C than in the other groups. En bloc resection rates and median treatment times were 91.4% and 80 min in Group A, 91.1% and 97 min in Group B and 86.7% and 110 min in Group C, respectively. No significant differences were noted between groups, or for en bloc resection rate and treatment time according to tumour size and location, or between groups for frequency of complications. CONCLUSIONS: ESD for gastric neoplasms is effective and safe in elderly patients, and may be positively recommended to elderly patients with intramucosal gastric neoplasms.
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Dissecação/métodos , Mucosa Gástrica/cirurgia , Gastroscopia/métodos , Neoplasias Gástricas/cirurgia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adenoma/patologia , Adenoma/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia , Perda Sanguínea Cirúrgica , Endossonografia , Estudos de Viabilidade , Feminino , Gastrectomia/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Hemorragia Pós-Operatória/etiologia , Estômago/lesões , Neoplasias Gástricas/patologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The epidemiology and pathophysiology of non-erosive gastro-oesophageal reflux disease differs from erosive gastro-oesophageal reflux disease. There is a possibility that non-erosive gastro-oesophageal reflux disease treatment requires a different regimen/approach but it is not yet acknowledged. AIM: To investigate the efficacy of famotidine and omeprazole in the treatment of gastro-oesophageal reflux disease, especially non-erosive gastro-oesophageal reflux disease. PATIENTS AND METHODS: A randomized, open-label trial was conducted. Fifty-four gastro-oesophageal reflux disease patients were assigned to treatment with famotidine at a dosage of 20 mg twice daily; or omeprazole, 20 mg once daily, for a period of 8 weeks. The Short Form-36 Health Survey and Gastrointestinal Symptom Rating Scale administered at baseline and after 8 weeks of treatment as well as a symptom questionnaire were conducted daily. RESULTS: Short Form-36 revealed that gastro-oesophageal reflux disease has severe impact on health-related quality of life. Thirty-nine subjects (77%) were endoscopically diagnosed as non-erosive gastro-oesophageal reflux disease. The mean Gastrointestinal Symptom Rating Scale abdominal pain, and indigestion score of non-erosive gastro-oesophageal reflux disease significantly improved in famotidine-treated patients (P < 0.05), but not in the omeprazole. There was no significant change regarding improved heartburn symptoms of non-erosive gastro-oesophageal reflux disease between treatments in the daytime or night-time. CONCLUSION: Famotidine and omeprazole were both effective in improving symptoms of gastro-oesophageal reflux disease, particularly non-erosive gastro-oesophageal reflux disease.
Assuntos
Antiulcerosos/administração & dosagem , Famotidina/administração & dosagem , Refluxo Gastroesofágico/tratamento farmacológico , Omeprazol/administração & dosagem , Análise de Variância , Quimioterapia Combinada , Feminino , Azia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Inquéritos e Questionários , Resultado do TratamentoRESUMO
AIMS: Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. METHODS: Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg.kg(-1).day(-1)) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg.kg(-1).day(-1) for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor beta, beta-inducible gene-h3 and nephrin were also quantitated. RESULTS: Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFbeta and betaig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. CONCLUSION/INTERPRETATION: These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Nefropatias Diabéticas/prevenção & controle , Rim/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Perindopril/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Hipertensão/genética , Imuno-Histoquímica , Rim/citologia , Rim/patologia , Masculino , Proteínas de Membrana , Proteínas/metabolismo , Ratos , Ratos Endogâmicos SHR , Valores de ReferênciaRESUMO
In both the natriuretic peptide and renin-angiotensin systems, peptidases play an important role in the inactivation or activation of the system. Angiotensin-converting enzyme is responsible for the conversion of angiotensin I to angiotensin II, while neutral endopeptidase is one of the pathways involved in the degradation of the natriuretic peptides. The vasopeptidase inhibitors, which simultaneously inhibit neutral endopeptidase and angiotensin-converting enzyme, appear to offer distinct therapeutic advantages in treating hypertension, heart failure, and endothelial dysfunction.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cardiotônicos/farmacologia , Endotélio Vascular/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Coração/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Falência Renal Crônica/etiologia , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
OBJECTIVE: To assess the in-vivo action on the renal microvasculature of the calcium antagonists nifedipine (L-type blocker), efonidipine (L/T-type blocker), and mibefradil (predominant T-type blocker). DESIGN: An intravital needle-type charge-coupled device (CCD) camera videomicroscope was introduced to visualize the renal microcirculation directly in vivo. METHODS: In anesthetized mongrel dogs, nifedipine (0.01-1 mg/kg per min), efonidipine (0.033-0.33 mg/kg per min), or mibefradil (0.01-1 mg/kg per min) was infused intravenously after the insertion of a CCD probe into the kidney. Renal microvascular responses to calcium antagonists were directly evaluated, with concomitant observation of renal clearance. RESULTS: Each calcium antagonist caused modest vasodepressor action without affecting heart rate. Nifedipine (1 mg/kg per min, n = 9) increased renal plasma flow (RPF) (14 +/- 4%, P < 0.05) and glomerular filtration rate (GFR) (19 +/- 5%, P < 0.05), and tended to increase the filtration fraction (5 +/- 2% increment, P = 0.07). Efonidipine (0.33 mg/kg per min, n = 9), however, had no effect on filtration fraction, with 14 +/- 6% increments in RPF (P < 0.05) and 14 +/- 7% increments in GFR (P = 0.08). Rather, mibefradil (1 mg/kg per min, n = 9) elicited 6 +/- 2% decreases in filtration fraction (P < 0.05), with slight increments in RPF (6 +/- 3%) and no changes in GFR. In direct in-vivo microvasculature observations, nifedipine caused predominant (22 +/- 2%) dilatation of afferent arterioles (from 15.5 +/- 0.4 to 18.9 +/- 0.4 microm, n = 5), compared with that of efferent arterioles (10 +/- 2%; from 11.0 +/- 0.4 to 12.1 +/- 0.3 microm). In contrast, efonidipine caused a similar magnitude of vasodilatation (16 +/- 4%) compared with 18 +/- 2%; n = 6), and mibefradil caused greater dilatation of efferent arterioles (20 +/- 4%, n = 7) than that of afferent arterioles (13 +/- 4%). CONCLUSIONS: There exists marked heterogeneity in action of nifedipine, efonidipine and mibefradil on the renal microvascular in canine kidneys in vivo. Furthermore, our current observations suggest an important contribution of T-type calcium channel activity to efferent arteriolar tone in vivo.
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Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo T/efeitos dos fármacos , Nitrofenóis , Circulação Renal/efeitos dos fármacos , Vasodilatação , Animais , Di-Hidropiridinas/farmacologia , Cães , Hemodinâmica/efeitos dos fármacos , Mibefradil/farmacologia , Microcirculação/efeitos dos fármacos , Nifedipino/farmacologia , Compostos Organofosforados/farmacologiaRESUMO
This study examined the effects of different types of calcium channel antagonists on renal haemodynamics and natriuresis. The intravenous infusion of nifedipine (L-type blocker), efonidipine (L/T-type blocker) or mibefradil (predominant T-type blocker) into anaesthetized dogs elicited similar, albeit modest, reductions in blood pressure. Nifedipine (1 microgram.min(-1).kg(-1)) increased renal plasma flow (RPF) (23+/-6%; P<0.05) and glomerular filtration rate (GFR) (25+/-5%; P<0.05) (all values are means+/-S.E.M., n=7). Efonidipine (0.33 microgram .min(-1).kg(-1)) also elevated RPF (18+/-6%; P<0.05), and tended to increase GFR (17+/-8%; P=0.08). These antagonists exerted contrasting actions on the filtration fraction (FF), with an increase being elicited by nifedipine, whereas efonidipine had no effect. Furthermore, mibefradil (0.01-1 microgram.min(-1).kg(-1)) slightly elevated RPF (between 5+/-3% and 8+/-3%), but failed to alter GFR, resulting in a decrease in FF. Nifedipine slightly increased urinary sodium excretion (U(Na)V) (29+/-16% increase at 1 microgram .min(-1).kg(-1)) and fractional sodium excretion (FE(Na)) (18+/-14%), whereas efonidipine (0.33 microgram .min(-1).kg(-1)) elicited marked elevations in U(Na)V (110+/-38%; P<0.05) and FE(Na) (102+/-44%; P<0.05). Mibefradil (1 microgram .min(-1).kg(-1)) exerted a moderate natriuretic action [U(Na)V, +60+/-32% (P=0.1); FE(Na), +67+/-20% (P<0.05)]. Furthermore, although a positive correlation was observed between U(Na)V and urinary nitrate/nitrite excretion, no differences were noted between the various calcium channel antagonists. Collectively, this study demonstrates that the glomerular haemodynamic and natriuretic actions of these calcium channel antagonists, which possess diverse blocking activities on L/T-type channels, vary. Based on the divergent actions on FF (i.e. increase, no change and decrease by nifedipine, efonidipine and mibefradil respectively), the natriuretic action of calcium channel antagonists is possibly attributed to the inhibition of tubular sodium reabsorption associated with increased post-glomerular blood flow, rather than increased GFR.
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Bloqueadores dos Canais de Cálcio/farmacologia , Natriurese/efeitos dos fármacos , Nitrofenóis , Circulação Renal/efeitos dos fármacos , Animais , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo T/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Cães , Relação Dose-Resposta a Droga , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Masculino , Mibefradil/farmacologia , Natriurese/fisiologia , Nifedipino/farmacologia , Óxido Nítrico/urina , Compostos Organofosforados/farmacologia , Prostaglandinas/urinaRESUMO
OBJECTIVES: Vasopeptidase inhibitors are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). The aim of this study was to characterize in-vitro and in-vivo inhibition of NEP and ACE in the rat with the vasopeptidase inhibitor gemopatrilat. DESIGN AND METHODS: In-vitro NEP and ACE inhibition was studied by radioinhibitory binding assay using rat renal membranes and the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A, respectively (n = 3 per curve). In-vivo NEP and ACE inhibition was studied using in-vitro autoradiography in rats that received oral gemopatrilat (1, 3, 10 mg/kg; n = 4 per dose) and were killed 1 h later, or received oral gemopatrilat (3, 10 mg/kg) and were killed at time points 1, 2, 4, 8, 18, 24 and 48 h (n = 4 per time point). RESULTS: Gemopatrilat caused a concentration-dependent displacement of specific radioligands from renal membrane NEP (IC50 305 +/- 5.4 nmol/I) and ACE (IC50 3.6 +/- 0.02 nmol/). In the dose-response study gemopatrilat (1, 3 and 10 mg/kg) caused significant inhibition of plasma ACE (P< 0.01), and renal ACE and NEP (3, 10 mg/kg, P < 0.01). In the time course experiment, gemopatrilat (10 mg/kg) increased plasma renin activity for 8 h (P< 0.01) and inhibited plasma ACE (P< 0.05), renal NEP (P< 0.01) and renal ACE (P< 0.05) for 48 h. CONCLUSIONS: Gemopatrilat is a potent in-vitro vasopeptidase inhibitor that also causes prolonged inhibition of circulating and renal ACE and renal NEP after a single oral dose. The data suggest that gemopatrilat may be a useful addition to existing vasopeptidase inhibitors in the treatment of cardiovascular disease.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores Enzimáticos/farmacologia , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Administração Oral , Animais , Ligação Competitiva , Dipeptídeos/metabolismo , Relação Dose-Resposta a Droga , Técnicas In Vitro , Radioisótopos do Iodo , Iodobenzenos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/metabolismoRESUMO
BACKGROUND: A noninvasive technique to monitor renal microcirculation would be a useful tool for investigation of renal disease and the effects of drugs on the renal system. We have developed a novel, less invasive technique to visualize renal microcirculation in vivo using an intravital tapered-tip (1 mm phi) lens-probe (pencil lens-probe) videomicroscopy, which only requires insertion of the probe into superficial renal cortex in situ. METHODS: To assess validity of this technique, the effects of angiotensin II (Ang II) and intrarenal sodium chloride loading (activator of tubuloglomerular mechanism) were examined. The renal microvasculature was successfully visualized and monitored. RESULTS: Administration of Ang II (1, 3, 10 and 30 ng/kg/min) produced a dose-dependent constriction of afferent and efferent arterioles in similar degrees; at 30 ng/kg/min, Ang II elicited 52 +/- 3 (N = 9) and 53 +/- 3% decreases in diameter (N = 9), respectively. The Ang II-induced arteriolar constriction was completely prevented by losartan, an Ang II type 1 (AT1) antagonist. The intrarenal hypertonic saline administration elicited transient increments (from 98 +/- 8 to 122 +/- 7 mL/min, N = 6, P < 0.05), followed by a marked reduction in renal blood flow (RBF; 78 +/- 7 mL/min, P < 0.05). This response was accompanied by prominent constriction of afferent (from 15.0 +/- 1.1 to 8.5 +/- 1.1 microm, N = 6, P < 0.05), but not efferent (from 14.3 +/- 1.2 to 13.8 +/- 1.0 microm, N = 3) arterioles. Furthermore, this response was completely inhibited by furosemide, a tubuloglomerular feedback inhibitor. CONCLUSION: : The intravital pencil lens-probe videomicroscopy can be a powerful tool for in vivo observation of renal microcirculation, with intact renal microvascular responses to two important renal homeostatic mechanisms, angiotensin II and tubuloglomerular feedback.
Assuntos
Anticoagulantes/uso terapêutico , Citratos/uso terapêutico , Terapia de Substituição Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Citratos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Substituição Renal/efeitos adversos , Estudos Retrospectivos , Citrato de Sódio , Análise de SobrevidaRESUMO
OBJECTIVES: To identify one of the possible factors responsible for periodontal disease in Down's syndrome (trisomy 21) patients, we studied the enzyme activity and the mRNA expression pattern of matrix metalloproteinases (MMPs) of cultured gingival fibroblasts (GF) and fresh gingival tissues. MATERIALS AND METHODS: Gingival tissue was used as the cell source and was biopsied at the time of dental treatment from nine patients with Down's syndrome and nine non-Down's controls. GF were cultivated in serum-free media for analyses of their MMP activities at the transcription or the protein level. The MMP activities in the supernates were measured by gelatin impregnated zymography. Relative levels of MMP mRNA from the cultured GF or freshly isolated gingival tissues were determined using the reverse transcription polymerase chain reaction (RT-PCR). RESULT AND CONCLUSIONS: The production of the active type of MMP-2 in GF from Down's syndrome patients (D-GF) was found to be significantly higher (P < 0.05) than that of the control GF (C-GF) at the protein level. The mRNA expressions of membrane-type I MMP (MT1-MMP) and MMP-2 in D-GF were constitutively augmented when compared with those of C-GF. These findings suggest that specific increase of the active form of MMP-2 in D-GF may possibly be due to the concomitant expression of MT1-MMP in the cultured cells, and this could be related to the pathogenesis of gingivitis/periodontitis associated with Down's syndrome patients.
Assuntos
Síndrome de Down/complicações , Síndrome de Down/enzimologia , Metaloproteinase 2 da Matriz/metabolismo , Periodontite/enzimologia , Periodontite/etiologia , Adolescente , Adulto , Análise de Variância , Western Blotting , Estudos de Casos e Controles , Criança , Eletroforese em Gel de Poliacrilamida/métodos , Ensaio de Imunoadsorção Enzimática , Feminino , Fibroblastos/enzimologia , Gengiva/citologia , Gengiva/enzimologia , Humanos , Masculino , Metaloproteinases da Matriz Associadas à Membrana , Metaloendopeptidases/biossíntese , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
To identify cartilage-degrading enzymes and cell types that can be specifically induced by interleukin-1 (IL-1)alpha, we studied matrix metalloproteinase (MMP) activities of cultured rat temporomandibular joint (TMJ) chondrocytes and disc cells. The cells were isolated from TMJs pre-injected with normal physiological saline (CR) or recombinant human IL-1alpha (AR). MMP activities in the conditioned media were assayed by gelatin enzymography, and they were identified by Western blot analyses. MMP mRNAs in these cells were also detected by RT-PCR. IL-1alpha significantly induced an increase of active MMP9 as well as pro- and active MMP3, but had no effect on the MMP2 activity in both types of cells. MMP3 and MMP9 mRNAs were also inducible in these cells by IL-1alpha stimulation. Furthermore, disc cells were more susceptible to IL-1alpha than chondrocytes. AR cells spontaneously produced the same MMPs in vitro as the CR cells synthesized under IL-1alpha stimulation. The results indicate that MMP9 and MMP3 were predominantly produced by disc cells, and these may be considered to play a pivotal role in ECM degradation during pathological conditions of the TMJ, such as IL-1-induced TMJ arthritis.
Assuntos
Indução Enzimática/efeitos dos fármacos , Interleucina-1/farmacologia , Metaloproteinases da Matriz/biossíntese , Articulação Temporomandibular/enzimologia , Análise de Variância , Animais , Western Blotting , Células Cultivadas , Condrócitos/enzimologia , Eletroforese em Gel de Poliacrilamida , Humanos , Interleucina-1/fisiologia , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 3 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , RNA Mensageiro/análise , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Articulação Temporomandibular/citologia , Disco da Articulação Temporomandibular/citologia , Disco da Articulação Temporomandibular/enzimologiaRESUMO
The occurrence of neurogenic pulmonary edema (NPE) associated with subarachnoid hemorrhage (SAH) due to ruptured aneurysm was analyzed in 48 consecutive patients. Correlations of the location of the aneurysm, clinical grade, amount of subarachnoid clot, and severity of NPE were examined. NPE was observed in 29.4% of all SAH cases, but the incidence was significantly higher in cases of ruptured vertebral artery (VA) aneurysm. Clinical grade, severity of NPE, and deformation of the medulla oblongata were studied in the five cases of ruptured VA aneurysm. Deformation of the ventrolateral medulla oblongata was observed in all patients. Asymmetry index of the medulla oblongata measured on the axial computed tomography scan was correlated with the severity of NPE. Severity of NPE tended to correlate with deformation of the medulla oblongata. NPE associated with ruptured VA aneurysm is caused by deformation of the ventrolateral site of the medulla oblongata by the localized hemorrhage.
Assuntos
Aneurisma Roto/complicações , Aneurisma Intracraniano/complicações , Bulbo/irrigação sanguínea , Edema Pulmonar/etiologia , Hemorragia Subaracnóidea/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Glicemia/análise , Catecolaminas/sangue , Catecolaminas/metabolismo , Feminino , Humanos , Hipotálamo/fisiopatologia , Incidência , Masculino , Bulbo/patologia , Bulbo/fisiopatologia , Pessoa de Meia-Idade , Edema Pulmonar/epidemiologia , Edema Pulmonar/fisiopatologia , Ruptura EspontâneaRESUMO
Athymic cytokine receptor gamma chain mutant mice that lack the thymus, Peyer's patches, cryptopatches (CP), and intestinal T cells were reconstituted with wild-type bone marrow cells. Bone marrow-derived TCR(-) intraepithelial lymphocytes (IEL) first appeared within villous epithelia of small intestine overlying the regenerated CP, and these TCR(-) IEL subsequently emerged throughout the epithelia. Thereafter, TCR(+) IEL increased to a comparable number to that in athymic mice and consisted of TCRgammadelta and TCRalphabeta IEL. In gut-associated lymphoid tissues of wild-type mice, only CP harbored a large population of c-kit(high)IL-7R(+)CD44(+)Thy-1(+/-)CD4(+/-)CD25(low/-)alpha(E) beta(7)(-)Lin(-) (Lin, lineage markers) lymphocytes that included cells expressing germline but not rearranged TCRgamma and TCRbeta gene transcripts. These findings provide direct evidence that gut CP develop progenitor T cells for extrathymic IEL descendants.