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1.
Mediators Inflamm ; 2019: 8474523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827383

RESUMO

We previously reported that acute necrotizing pancreatitis (ANP) after normal or high-fat diet is associated with a decreased number of Paneth cells in ileal crypts. Here, we ablated Paneth cells in a rat model of ANP after normal and high-fat diet to investigate the effects on disease symptoms. Adult male Sprague-Dawley rats received standard rat chow or a high-fat diet for 2 weeks, after which they were treated with dithizone to deplete Paneth cells. Six hours later, ANP was established by retrograde injection of sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at 6, 12, and 24 h for assessment. We found dithizone aggravated ANP-associated pathological injuries to the pancreas and ileum in rats on high-fat or standard diets. Lysozyme expression in ileal crypts was decreased, while serum inflammatory cytokines (TNFα, IL-1ß, and IL-17A) and intestinal permeability (serum DAO activity and D-lactate) were increased. Expression of tight junction proteins (claudin-1, zo-1, and occludin) was decreased. Using high-throughput 16S rRNA sequencing, we found dithizone reduced microbiota diversity and altered microbiota composition in rats on high-fat or standard diets. Dithizone decreased fecal short-chain fatty acids (SCFAs) in rats on high-fat or standard diets. Changes in intestinal microbiota correlated significantly with SCFAs, lysozyme, DAO activity, D-lactate, inflammatory cytokines, and pathological injury to the pancreas and ileum in rats on high-fat or standard diets. In conclusion, ablation of Paneth cells exacerbates pancreatic and intestinal injuries in ANP after normal and high-fat diet. These symptoms may be related to changes in the intestinal microbiota.


Assuntos
Ditizona/farmacologia , Ditizona/uso terapêutico , Pancreatite Necrosante Aguda/metabolismo , Celulas de Paneth/efeitos dos fármacos , RNA Ribossômico 16S/metabolismo , Animais , Western Blotting , Dieta Hiperlipídica , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Intestinos/efeitos dos fármacos , Intestinos/lesões , Masculino , Muramidase/efeitos dos fármacos , Muramidase/metabolismo , Pancreatite Necrosante Aguda/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Ácido Taurocólico/farmacologia
2.
Seizure ; 18(1): 51-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18703360

RESUMO

Zinc has been proven to be anticonvulsant in several studies which indicate that diphenylthiocarbazone (dithizone) and diethyldithiocarbamate (DEDTC), zinc chelating agents, enhance seizure activities. There is also evidence that nitric oxide (NO) generators increase zinc concentration in the brain. On the other hand, the increased level of NO in the nervous system and the consequently increased seizure threshold in cholestatic mice have been well studied. Thus, it could be hypothesized that one of the reasons for the increased seizure threshold in cholestasis is partly the enhanced endogenous zinc concentration, at least in part, due to the overproduction of NO. In this study, we examined the hypothesis that zinc chelating agents might decrease seizure activity to its pre-cholestatic level in bile duct-ligated (BDL) mice. Mice were intra-peritoneally injected with dithizone and diethyldithiocarbamate (DEDTC) before the induction of seizure by pentylenetetrazole (PTZ) and then the seizure activity was recorded. Dose response (dithizone: 5, 30, 100 and 200mg/kg; DEDTC: 25, 50 and 100mg/kg) and time course (only for dithizone: 15, 30, 60 and 120 min) studies were performed first. Then, the effects of cholestasis, with and without dithizone injection, on seizure activity were assessed. Proconvulsant effect of dithizone and DEDTC was proved to be dose dependent although time interval between dithizone and PTZ injections did not play any significant role in the seizure activity. Cholestasis decreased seizure activity and increased lag phase before seizure and both effects were decreased by dithizone injection. It is elicited that zinc may mediate the cholestasis-induced decrement in seizure activity.


Assuntos
Quelantes/uso terapêutico , Colestase/tratamento farmacológico , Ditizona/uso terapêutico , Ditiocarb/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Animais , Ductos Biliares/efeitos dos fármacos , Colestase/complicações , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Pentilenotetrazol , Convulsões/complicações , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Fatores de Tempo
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