Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Mais filtros

Base de dados
Intervalo de ano de publicação
Arch Toxicol ; 93(10): 2863-2878, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444509


Acetaminophen (APAP)-induced liver injury is the main cause of acute liver failure. This study investigated the role of microsomal prostaglandin E synthase 2 (mPGES-2), discovered as one of the prostaglandin E2 (PGE2) synthases, in mediating APAP-induced liver injury. Using mPGES-2 wild-type (WT) and knockout (KO) mice, marked resistance to APAP-induced liver damage was found in mPGES-2 KO, as indicated by robust improvement of liver histology, changes in liver enzyme release, and marked decrease in APAP-cysteine adducts (APAP-CYS) and inflammatory markers. Moreover, the results confirmed that increase in liver PGE2 content in KO mice under basal conditions was not critical for the protection from APAP-induced liver injury. Importantly, mPGES-2 deletion inhibited the production of malondialdehyde (MDA), increasing glutathione (GSH) level. Enhanced GSH level may contribute to the inhibition of APAP toxicity in mPGES-2 KO mice. To further elucidate the role of mPGES-2 in the liver injury induced by APAP, adeno-associated viruses (AAV) were used to overexpress mPGES-2 in the liver. The results showed that mPGES-2 overexpression aggravates liver injury associated with an increase in inflammatory markers and chemokines after APAP treatment. Moreover, a lower level of GSH was detected in the mPGES-2 overexpression group compared to the control group. Collectively, our findings indicate that mPGES-2 plays a critical role in regulating APAP-induced liver injury, possibly by regulating GSH and APAP-CYS level, which may provide a potential therapeutic strategy for the prevention and treatment of APAP-induced liver injury.

Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(1): 251-257, 2018 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-29397853


OBJECTIVE: To investigate the effect of MicroRNA-3963(miR-3963) on the adipogenic differentiation of mouse bone-derived mesenchymal stem cells(MSC). METHODS: MSCs were isolated from C57BL/6 mice bone fragment and transfected with miR-3963 mimic, miR-3963 inhibitor and negative control. The expression of miR-3963 and transfection efficiency were detected by q-PCR. These transfected cells were induced to adipocytes and stained with oil red O after 14 days culture. q-PCR and Western blot were used to detect the expression of adipogenic differentiation marker genes C/EBPα and PPARγ at transcriptional level and protein level. RESULTS: The results of q-PCR revealed that miR-3963 expression level was up-regulated after transfection with miR-3963 mimic (P<0.0001), and down-regulated after transfection with miR-3963 inhibitor (P<0.0001). After oil red staining, overexpression of miR-3963 in MSCs could promote the formation of lipid droplet. The q-PCR and Western blot analyses showed the significant increase of expression of adipogenic marker genes C/EBPα and PPARγ in MSC transfected with miR-3963 mimic. Additionally, compared with the control group, miR-3963 inhibitor could decrease adipogenic differentiation of MSC. CONCLUSION: miR-3963 can regulate and promote adipogenic differentiation of mouse bone-derived MSC.

Adipogenia , Adipócitos , Animais , Células Cultivadas , Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs
Food Funct ; 9(1): 389-396, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29215110


Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by massive enlargement of fluid-filled cysts in the kidney. There is an urgent need to develop effective ADPKD therapies. We used an in vitro Madin-Darby canine kidney (MDCK) cyst model and a murine embryonic kidney cyst model to evaluate whether quercetin inhibits cyst development. We then used a polycystic kidney disease (PKD) mouse model to further determine the in vivo effects of quercetin (100 mg per kg body weight twice per day) on PKD mice via subcutaneous injections. The results show that quercetin significantly and dose-dependently inhibited cyst formation and enlargement in the MDCK cyst and embryonic kidney cyst models. Quercetin also noticeably reduced the cystic index in PKD mice. Furthermore, the effective dose of quercetin did not cause cytotoxicity in MDCK cells. Quercetin treatment decreased the levels of intracellular signalling proteins in PKD mouse kidneys, including phosphorylated protein kinase B (also known as AKT) and phosphorylated extracellular signal-regulated kinase (ERK), which are upregulated and promote cyst development in ADPKD. Quercetin also reversed E-cadherin expression, which is localized in normal proximal tubules in PKD mouse kidneys. Taken together, these results demonstrate that quercetin hinders renal cyst development in vivo and in vitro and represents a novel candidate strategy for the treatment of ADPKD.

Rim Policístico Autossômico Dominante/tratamento farmacológico , Quercetina/administração & dosagem , Animais , Cistos/tratamento farmacológico , Cistos/embriologia , Cistos/genética , Modelos Animais de Doenças , Cães , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Infusões Parenterais , Rim/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Rim Policístico Autossômico Dominante/embriologia , Rim Policístico Autossômico Dominante/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo
Biomed Pharmacother ; 96: 328-335, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29024899


Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. The progression of NAFLD is complex and associated with inflammation, oxidative stress, autophagy, endoplasmic reticulum stress, and insulin resistance. Mangiferin, a natural C-glucosyl xanthone, has been reported to show multiple biological activities. The aim of this study was to investigate the therapeutic effect of mangiferin on NAFLD and the underlying molecular mechanism. We established a mouse model of NAFLD using a high-fat diet (HFD), and injected the mice with different doses of mangiferin (15, 30, and 60mg/kg, intraperitoneal) for 12 weeks. Liver tissue was assessed to evaluate changes in inflammatory responses, autophagy, and glycolipid metabolism. We found that mangiferin decreased body weight, as well as the levels of triglycerides and total cholesterol in plasma and the liver. It also increased glucose tolerance in HFD-fed mice. In addition, mangiferin decreased inflammatory responses by inhibiting the activities of nuclear factor kappa B and c-Jun N-terminal kinase, regulated autophagy via the AMP-activated protein kinase/mechanistic target of rapamycin signaling pathway, and improved glycolipid metabolism via modulation of the insulin receptor substrate/phosphoinositide 3-kinase/protein kinase B signaling pathway. This study demonstrated that mangiferin significantly ameliorates NAFLD development in HFD-fed mice by inhibiting inflammatory responses, activating autophagy, and improving glycolipid metabolism.

Autofagia/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Xantonas/uso terapêutico , Animais , Autofagia/fisiologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Distribuição Aleatória , Xantonas/farmacologia
Cardiovasc Pathol ; 27: 37-42, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28081514


MiRNA-1 may participate in regulating ischemia-reperfusion injury (IRI) by affecting the expression and distribution of connexin 43 (Cx43). The aim of this study is to investigate miR-1 expression and its potential role in regulating Cx43 during ischemic postconditioning (IPOST) in a rat model. Fifty-five Wistar male rats were randomly divided into five groups: N, IR, IPOST, agomir-1, and antagomir-1 group. The hearts were perfused with the Langendorff system. The reperfusion arrhythmia (RA) and myocardial infarct size were observed and recorded. The miRNA-1 expression and the Cx43 expression and distribution were assessed by RT-PCR, immunoblotting, and immunohistochemistry. First, the RA score in the IR group was higher than that in the control group, whereas there was no difference between the IPOST and antagomir-1 groups. Second, the myocardial infarct size was larger in the agomir-1 than in the IPOST group; there was no difference between the antagomir-1 and the IPOST group. Third, the miRNA-1 expression increased by 78% in the agomir-1 group but decreased by 32% in the antagomir-1 group compared with the IPOST group. Fourth, compared with the Control group, the Cx43 expression in the IR group decreased, the Cx43 expression decreased in the agomir-1 group compared with the IPOST group. Fifth, the distribution of Cx43 was irregular and disorganized in the IR and agomir-1 groups. In the IPOST and antagomir-1 groups, Cx43 was neatly distributed in the intercalated disk area. Our findings suggest that IPOST can inhibit the up-regulation of miRNA-1 induced by ischemia-reperfusion and that the down-regulation of miRNA-1 can prevent the decrease and redistribution of Cx43, which will protect the heart from IRI.

Conexina 43/biossíntese , Regulação da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Animais , Western Blotting , Conexina 43/genética , Modelos Animais de Doenças , Imuno-Histoquímica , Pós-Condicionamento Isquêmico , Preparação de Coração Isolado , Masculino , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real