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2.
Pathol Int ; 68(1): 12-22, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29154469

RESUMO

Although several non-alcoholic steatohepatitis (NASH) models have been reported to date, few of these models fully reflect the histopathology and pathophysiology of human NASH. The aim of this study was to establish a novel NASH model by feeding a high-fat (HF) diet and administering both carbon tetrachloride (CCl4 ) and the Liver X receptor agonist T0901317. Male C57BL/6J mice were divided into four groups (each n = 5): HF, HF + CCl4 , HF + T0901317, and the novel NASH model (HF + CCl4 + T0901317). CCl4 (0.1 mL/kg) and T0901317 (2.5 mg/kg) were intraperitoneally administered four times and five times, respectively. The livers of the novel NASH model group presented a whitish colour. The serum levels of TNF-α and IL-6 were significantly increased in the novel NASH model group, and mice in this group exhibited histopathological features and insulin resistance reflective of NASH, i.e., macrovesicular hepatic steatosis, ballooning hepatocytes, Mallory-Denk bodies, lobular inflammation and fibrosis. The novel NASH model group presented significantly upregulated expression levels of mRNAs related to lipogenesis, oxidative stress, fibrosis and steatosis and significantly downregulated expression levels of mRNAs related to triglyceride export. We successfully established a novel experimental NASH model that exhibits similar histopathology and pathophysiology to human NASH.


Assuntos
Modelos Animais de Doenças , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Tetracloreto de Carbono/toxicidade , Dieta Hiperlipídica/efeitos adversos , Hidrocarbonetos Fluorados/toxicidade , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sulfonamidas/toxicidade
3.
Hepatol Res ; 46(7): 697-706, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26490536

RESUMO

AIM: Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. METHODS: Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. RESULTS: Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group. CONCLUSION: Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure.

4.
World J Gastroenterol ; 21(45): 12778-86, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26668502

RESUMO

AIM: To investigate the cytoprotective effects in hepatic ischemia-reperfusion injury, we developed a new formulation of hyaluronic acid (HA) and sphingosine 1-phophate. METHODS: We divided Sprague-Dawley rats into 4 groups: control, HA, sphingosine 1-phosphate (S1P), and HA-S1P. After the administration of each agent, we subjected the rat livers to total ischemia followed by reperfusion. After reperfusion, we performed the following investigations: alanine aminotransferase (ALT), histological findings, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, and transmission electron microscopy (TEM). We also investigated the expression of proteins associated with apoptosis, hepatoprotection, and S1P accumulation. RESULTS: S1P accumulated in the HA-S1P group livers more than S1P group livers. Serum ALT levels, TUNEL-positive hepatocytes, and expression of cleaved caspase-3 expression, were significantly decreased in the HA-S1P group. TEM revealed that the liver sinusoidal endothelial cell (LSEC) lining was preserved in the HA-S1P group. Moreover, the HA-S1P group showed a greater increase in the HO-1 protein levels compared to the S1P group. CONCLUSION: Our results suggest that HA-S1P exhibits cytoprotective effects in the liver through the inhibition of LSEC apoptosis. HA-S1P is an effective agent for hepatic ischemia/reperfusion injury.


Assuntos
Sistemas de Liberação de Medicamentos , Células Endoteliais/efeitos dos fármacos , Ácido Hialurônico/administração & dosagem , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Lisofosfolipídeos/administração & dosagem , Substâncias Protetoras/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Esfingosina/análogos & derivados , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/sangue , Química Farmacêutica , Citoproteção , Modelos Animais de Doenças , Combinação de Medicamentos , Células Endoteliais/metabolismo , Células Endoteliais/ultraestrutura , Heme Oxigenase (Desciclizante)/metabolismo , Ácido Hialurônico/química , Marcação In Situ das Extremidades Cortadas , Fígado/metabolismo , Fígado/ultraestrutura , Hepatopatias/sangue , Hepatopatias/patologia , Lisofosfolipídeos/química , Masculino , Microscopia Eletrônica de Transmissão , Substâncias Protetoras/química , Ratos Sprague-Dawley , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Esfingosina/administração & dosagem , Esfingosina/química
5.
Int J Mol Sci ; 16(6): 12051-63, 2015 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-26023714

RESUMO

Hepatocyte-specific Phosphatase and tensin homolog (Pten)-knockout (KO) mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). 1,8-cineole is a monoterpene oxide and it has several biological effects including hepatoprotective effects. In this study we revealed that 1,8-cineole ameliorates NASH of Pten KO mice. Pten KO mice were assigned to a control group without any medication or to a 1,8-cineole group injected with 50 mg/kg i.p. twice per week for eight weeks. At eight weeks, livers from each group were processed to measure triglyceride (TG) content, gene expression analysis, western blot analysis, and histological examination including Oil red O staining. 1,8-cineole ameliorated hepatic steatosis in Pten KO mice, revealed by TG content and Oil red O staining. Moreover, 1,8-cineole downregulated collagen 1a1 expression and improved liver fibrosis. Thus, 1,8-cineole has potential as a candidate to treat NASH by inactivating the Akt/PI3-kinase pathway.


Assuntos
Cicloexanóis/administração & dosagem , Fígado Gorduroso/tratamento farmacológico , Fígado/efeitos dos fármacos , Monoterpenos/administração & dosagem , PTEN Fosfo-Hidrolase/genética , Transdução de Sinais/efeitos dos fármacos , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cicloexanóis/farmacologia , Eucaliptol , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Injeções Intraperitoneais , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Monoterpenos/farmacologia , Especificidade de Órgãos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Triglicerídeos/metabolismo
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