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1.
Plants (Basel) ; 10(8)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34451680

RESUMO

Weigela subsessilis is used in folk medicine to treat pain and allergic syndromes in Korea. However, the antibacterial and anti-inflammatory activities of W. subsessilis callus extract remain unexplored. In this study, we aimed to evaluate the W. subsessilis callus of pharmacological activity. Therefore, we first established in vitro calluses of W.subsessilis via plant tissue culture methods. We then evaluated the antioxidant and anti-inflammatory effects of W. subsessilis callus extract in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells. The W. subsessilis callus extract showed antioxidant and anti-inflammatory effects. These effects were regulated via suppression of mitogen-activated protein kinase signaling through LPS-induced translocation of nuclear factor kappa B (NF-κB) p65 from the cytoplasm to the nucleus. W. subsessilis callus extract also showed antibacterial and anti-inflammatory activities in Propionibacterium acnes-treated HaCaT keratinocyte cells. These results indicate that W. subsessilis callus extract has antioxidant, antibacterial and anti-inflammatory activities, suggesting its possible application in the treatment of inflammatory disorders.

2.
Plants (Basel) ; 9(12)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287317

RESUMO

Toona sinensis has been traditionally used to treat dysentery, enteritis, flatulence, and itchiness. However, the existence of anti-inflammatory effects of T. sinensis on Propionibacterium acnes-induced skin disease is unknown. In vitro cultures of plant cells and tissues produced under controlled conditions offer a continuous production platform for plant natural products including pigments and anti-inflammatory agents. In this study, we determine the anti-inflammatory activities of an extract of in vitro grown adventitious shoots of T. sinensis on P. acnes, the etiologic agent of skin inflammation. The extract of T. sinensis showed antioxidant and anti-inflammatory activity in LPS-treated RAW264.7 cells. It also had antibacterial activity and anti-inflammatory effects on P. acnes-treated HaCaT cells. In addition, these effects were regulated by suppression of the mitogen-activated protein kinase (MAPK) pathways. These results suggesting the potential application of adventitious shoots of T. sinensis grown with an in vitro proliferation system as a medicine for treating P. acnes-induced inflammatory skin disease.

3.
Nat Prod Res ; 33(22): 3283-3286, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29726712

RESUMO

In this study, Auricularia auricula-judae (Bull.) extract (AAE) had potent antioxidant activity in vitro and promoted the biosynthesis of procollagen, a precursor of collagen in HaCaT cells. In addition, the expression of HAS-3 (hyaluronic acid synthase), which is a moisturizing factor, was increased in HaCaT cells in response to AAE. Therefore, this work suggests that AAE has the potential to exhibit antioxidant activity and promote procollagen biosynthesis in HaCaT cells.


Assuntos
Agaricales/química , Antioxidantes/isolamento & purificação , Pró-Colágeno/biossíntese , Antioxidantes/química , Antioxidantes/farmacologia , Basidiomycota , Linhagem Celular , Humanos , Hialuronan Sintases/efeitos dos fármacos , Hialuronan Sintases/metabolismo , Pró-Colágeno/efeitos dos fármacos , Pele/citologia , Pele/enzimologia , Pele/metabolismo
4.
PLoS One ; 13(12): e0209347, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566448

RESUMO

Whether preoperative spirometry in non-thoracic surgery can predict postoperative pulmonary complications (PPCs) is controversial. We investigated whether preoperative spirometry results can predict the occurrence of PPCs in patients who had undergone laparoscopic abdominal surgery. This retrospective observational study analyzed the records of patients who underwent inpatient laparoscopic gastric or colorectal cancer surgery at Seoul National University Bundang Hospital between January 2010 and June 2017. Preoperative spirometry was performed for patients at a high risk of PPCs, such as elderly patients (age >60 years), patients aged <60 years with chronic pulmonary disease, and current smokers. The main outcome was the association between the results of spirometry tests performed within 1 month prior to surgery and the occurrence of PPCs, as determined by multivariable logistic regression analysis. Of the 898 included patients who underwent laparoscopic gastric (372 patients) or colorectal cancer surgery (526 patients), PPC occurred in 117 patients (gastric cancer: 74, colorectal cancer: 43). A 1% greater preoperative forced vital capacity (FVC) was associated with a 2% lower incidence of PPCs after laparoscopic gastric or colorectal cancer surgery (odds ratio: 0.98, 95% confidence interval: 0.97-0.99, P = 0.018). However, the preoperative forced expiratory volume in 1 second (FEV1) (%) and FEV1/FVC (%) were not significantly associated with PPCs (P = 0.059 and P = 0.147, respectively). In conclusion, lower preoperative spirometry FVC, but not FEV1 or FEV1/FVC, may predict PPCs in high-risk patients undergoing laparoscopic abdominal surgery.


Assuntos
Laparoscopia/efeitos adversos , Pneumopatias/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Cuidados Pré-Operatórios/normas , Espirometria , Idoso , Feminino , Volume Expiratório Forçado , Humanos , Incidência , Pneumopatias/epidemiologia , Pneumopatias/etiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Cuidados Pré-Operatórios/métodos , Prognóstico , Estudos Retrospectivos , Capacidade Vital
5.
J Clin Med ; 7(6)2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29880755

RESUMO

High-sensitivity C-reactive protein (hsCRP) is a prognostic factor for hepatocellular carcinoma (HCC), while albumin is known to be a disease severity index of the malnutrition status in HCC patients. The present study investigated the association between postoperative hsCRP/albumin ratio and both overall survival (OS) and recurrence-free survival (RFS) following HCC surgery. This retrospective observational study examined the medical records of 389 patients who underwent resection for HCC between 2004 and 2013. Postoperative day 0⁻1 hsCRP/albumin ratio was collected, and the optimal postoperative mortality cut-off point was derived using receiver operating characteristics (ROC) analysis. A postoperative hsCRP/albumin ratio increase of 1.0 was associated with a 1.171-fold increase in mortality (hazard ratio (HR): 1.171, 95% confidence interval (CI): 1.072⁻1.278, p < 0.001) and a 1.19-fold increase in recurrence (HR: 1.190, 95% CI: 1.108⁻1.278, p < 0.001). The hsCRP/albumin ratio cut-off point was found to be 0.625 and 0.500. When patients were grouped by this cut-off point, the >0.625 group showed a 2.257-fold increase in mortality (HR: 2.257, 95% CI: 1.470⁻3.466, p < 0.001), and the >0.500 group showed a 1.518-fold increase in recurrence (HR: 1.518, 95% CI: 1.125⁻2.050, p = 0.006).

6.
Proc Natl Acad Sci U S A ; 115(16): 4152-4157, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29610354

RESUMO

Recent studies point out the link between altered mitochondrial metabolism and cancer, and detailed understanding of mitochondrial metabolism requires real-time detection of its metabolites. Employing heteronuclear 2D NMR spectroscopy and 13C3-pyruvate, we propose in-organelle metabolomics that allows for the monitoring of mitochondrial metabolic changes in real time. The approach identified acetyl phosphate from human mitochondria, whose production has been largely neglected in eukaryotic metabolism since its first description about 70 years ago in bacteria. The kinetic profile of acetyl phosphate formation was biphasic, and its transient nature suggested its role as a metabolic intermediate. The method also allowed for the estimation of pyruvate dehydrogenase (PDH) enzyme activity through monitoring of the acetyl-CoA formation, independent of competing cytosolic metabolism. The results confirmed the positive regulation of mitochondrial PDH activity by p53, a well-known tumor suppressor. Our approach can easily be applied to other organelle-specific metabolic studies.


Assuntos
Metabolômica/métodos , Mitocôndrias/metabolismo , Ressonância Magnética Nuclear Biomolecular/métodos , Organofosfatos/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Acrilatos/farmacologia , Sistemas Computacionais , Técnicas de Inativação de Genes , Genes p53 , Células HCT116 , Humanos , Fosforilação Oxidativa , Complexo Piruvato Desidrogenase/antagonistas & inibidores , Complexo Piruvato Desidrogenase/metabolismo , Proteína Supressora de Tumor p53/deficiência
7.
Diabetes Metab J ; 41(6): 474-485, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29199408

RESUMO

BACKGROUND: Regular aerobic exercise is essential for the prevention and management of type 2 diabetes mellitus and may be particularly beneficial for those treated with thiazolidinediones, since it may prevent associated weight gain. This study aimed to evaluate the effect of combined exercise and rosiglitazone treatment on body composition and glucose metabolism in obese diabetes-prone animals. METHODS: We analyzed metabolic parameters, body composition, and islet profiles in Otsuka Long Evans Tokushima Fatty rats after 28 weeks of aerobic exercise, rosiglitazone treatment, and combined exercise and rosiglitazone treatment. RESULTS: Combined exercise with rosiglitazone showed significantly less increase in weight and epididymal fat compared to rosiglitazone treatment. Aerobic exercise alone and combined rosiglitazone and exercise treatment led to similar retention of lean body mass. All experimental groups showed a decrease in fasting glucose. However, the combined exercise and rosiglitazone therapy group showed prominent improvement in glucose tolerance compared to the other groups. Rescue of islet destruction was observed in all experimental groups, but was most prominent in the combined therapy group. CONCLUSION: Regular aerobic exercise combined with rosiglitazone treatment can compensate for the adverse effect of rosiglitazone treatment and has benefit for islet preservation.

8.
Diabetes Metab J ; 40(5): 376-385, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27098507

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease is the most common form of chronic liver disease in industrialized countries. Recent studies have highlighted the association between peroxisomal dysfunction and hepatic steatosis. Peroxisomes are intracellular organelles that contribute to several crucial metabolic processes, such as facilitation of mitochondrial fatty acid oxidation (FAO) and removal of reactive oxygen species through catalase or plasmalogen synthesis. Statins are known to prevent hepatic steatosis and non-alcoholic steatohepatitis (NASH), but underlying mechanisms of this prevention are largely unknown. METHODS: Seven-week-old C57BL/6J mice were given normal chow or a methionine- and choline-deficient diet (MCDD) with or without various statins, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (15 mg/kg/day), for 6 weeks. Histological lesions were analyzed by grading and staging systems of NASH. We also measured mitochondrial and peroxisomal FAO in the liver. RESULTS: Statin treatment prevented the development of MCDD-induced NASH. Both steatosis and inflammation or fibrosis grades were significantly improved by statins compared with MCDD-fed mice. Gene expression levels of peroxisomal proliferator-activated receptor α (PPARα) were decreased by MCDD and recovered by statin treatment. MCDD-induced suppression of mitochondrial and peroxisomal FAO was restored by statins. Each statin's effect on increasing FAO and improving NASH was independent on its effect of decreasing cholesterol levels. CONCLUSION: Statins prevented NASH and increased mitochondrial and peroxisomal FAO via induction of PPARα. The ability to increase hepatic FAO is likely the major determinant of NASH prevention by statins. Improvement of peroxisomal function by statins may contribute to the prevention of NASH.

9.
FEBS Lett ; 589(7): 836-41, 2015 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-25728277

RESUMO

Tmem173 was identified as a growth inhibitor associated with major histocompatibility complex (MHC) class II and a potential stimulator for IFN-ß, an innate immune inducer and a negative feedback controller for RANKL-induced osteoclast differentiation of monocytic macrophage cells. In this study, we confirmed that transmembrane protein 173 (Tmem173) overexpression inhibited the expression of osteoclast-specific genes, tartrate-resistant acid phosphatase (TRAP), cathepsin K, and matrix metalloproteinase-9 (MMP-9), as well as bone resorption pit formation in RANKL-treated RAW 264.7 cells. Activation of osteoclast-specific transcription factors, c-Fos and nuclear factor of activated T cells cytoplasmic-1 (NFATc1), and RANKL-induced activation of ERK were also down-regulated by Tmem173 overexpression. Collectively, these results suggest that Tmem173 plays a regulatory role in RANKL-RANK-mediated signaling in osteoclastogenesis.


Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Osteoclastos/metabolismo , Ligante RANK/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Regulação da Expressão Gênica , Camundongos , Osteoclastos/citologia , Osteoprotegerina/metabolismo , Ligante RANK/genética , Transdução de Sinais
10.
Endocrinology ; 155(6): 2089-101, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24684302

RESUMO

The present study examined the role of clusterin in insulin resistance in high fat-fed wild-type and clusterin knockout (KO) mice. The plasma levels of glucose and C-peptide and islet size were increased in clusterin KO mice after an 8-week high-fat diet. In an ip glucose tolerance test, the area under the curve for glucose was not different, whereas the area under the curve for insulin was higher in clusterin KO mice. In a hyperinsulinemic-euglycemic clamp, the clamp insulin levels were higher in clusterin KO mice after the high-fat diet. After adjusting for the clamp insulin levels, the glucose infusion rate, suppression of hepatic glucose production, and glucose uptake were lower in clusterin KO mice in the high fat-fed group. The plasma levels of clusterin and clusterin mRNA levels in the skeletal muscle and liver were increased by the high-fat diet. The mRNA levels of the antioxidant enzymes were lower, and the mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 1 and cytokines and protein carbonylation were higher in the skeletal muscle and liver in clusterin KO mice after the high-fat diet. Palmitate-induced gene expressions of NOX1 and cytokines were higher in the primary cultured hepatocytes of clusterin KO mice compared with the wild-type mice. Clusterin inhibited the gene expression and reactive oxygen species generation by palmitate in the hepatocytes and C2C12. AKT phosphorylation by insulin was reduced in the hepatocytes of clusterin KO mice. These results suggest that clusterin plays a protective role against high-fat diet-induced insulin resistance through the suppression of oxidative stress and inflammation.


Assuntos
Clusterina/genética , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina/fisiologia , Animais , Peso Corporal/genética , Peso Corporal/fisiologia , Células Cultivadas , Clusterina/deficiência , Clusterina/metabolismo , Citometria de Fluxo , Teste de Tolerância a Glucose , Hepatócitos/metabolismo , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Carbonilação Proteica , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
Biochem Biophys Res Commun ; 445(3): 645-50, 2014 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-24569077

RESUMO

Clusterin induces the expression of various chemotactic cytokines including tumor necrosis factor-α (TNF-α) in macrophages and is involved in the cell migration. According to the results of this study, clusterin induced the directional migration (chemotaxis) of macrophages based on a checkerboard analysis. The chemotactic activity of clusterin was prevented by pretreatment with pertussis toxin (PTX), indicating that the Gαi/o-protein coupled receptor (GPCR) was involved in the chemotactic response of clusterin. Clusterin-stimulated chemotaxis was abrogated in a dose-dependent manner by pretreatment with gallein (a Gßγ inhibitor), indicating the involvement of Gßγ released from the GPCR. In addition, inhibitors of phospholipase C (PLC, U73122) and phosphoinositide 3-kinase (PI3K, LY294002), the key targets of Gßγ binding and activation, suppressed chemotactic migration by clusterin. The phosphorylation of Akt induced by clusterin was blocked by pretreatment with gallein or LY294002 but not with U73122, indicating that Gßγ released from the PTX-sensitive Gi protein complex activated PLC and PI3K/Akt signaling pathways separately. The activation of cellular MAP kinases was essential in that their inhibitors blocked clusterin-induced chemotaxis, and Gßγ was required for the activation of MAP kinases because gallein reduced their phosphorylations induced by clusterin. In addition, the inflammation-induced migration of macrophages was greatly reduced in clusterin-deficient mice based on a thioglycollate-induced peritonitis model system. These results suggest that clusterin stimulates the chemotactic migration of macrophages through a PTX-sensitive GPCR and Gßγ-dependent pathways and describe a novel role of clusterin as a chemoattractant of monocytes/macrophages, suggesting that clusterin may serve as a molecular bridge between inflammation and its remodeling of related tissue by recruiting immune cells.


Assuntos
Quimiotaxia , Clusterina/metabolismo , Macrófagos/citologia , Receptores Acoplados a Proteínas G/metabolismo , Animais , Quimiotaxia/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Toxina Pertussis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de Sinais , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismo
12.
Am J Chin Med ; 42(1): 173-87, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24467543

RESUMO

Ginseng has beneficial effects in cancer, diabetes and aging. There are two main varieties of ginseng: Panax ginseng (Korean ginseng) and Panax quinquefolius (American ginseng). There are anecdotal reports that American ginseng helps reduce body temperature, whereas Korean ginseng improves blood circulation and increases body temperature; however, their respective effects on body temperature and metabolic parameters have not been studied. We investigated body temperature and metabolic parameters in mice using a metabolic cage. After administering ginseng extracts acutely (single dose of 1000 mg/kg) or chronically (200 mg/kg/day for four weeks), core body temperature, food intake, oxygen consumption and activity were measured, as well as serum levels of pyrogen-related factors and mRNA expression of metabolic genes. Acute treatment with American ginseng reduced body temperature compared with PBS-treated mice during the night; however, there was no significant effect of ginseng treatment on body temperature after four weeks of treatment. VO 2, VCO 2, food intake, activity and energy expenditure were unchanged after both acute and chronic ginseng treatment compared with PBS treatment. In acutely treated mice, serum thyroxin levels were reduced by red and American ginseng, and the serum prostaglandin E2 level was reduced by American ginseng. In chronically treated mice, red and white ginseng reduced thyroxin levels. We conclude that Korean ginseng does not stimulate metabolism in mice, whereas a high dose of American ginseng may reduce night-time body temperature and pyrogen-related factors.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Dinoprostona/sangue , Consumo de Oxigênio/efeitos dos fármacos , Panax , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Tiroxina/sangue , Tecido Adiposo Marrom/metabolismo , Administração Oral , Animais , Circulação Sanguínea/efeitos dos fármacos , Dióxido de Carbono/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ginsenosídeos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Panax/classificação , Extratos Vegetais/química , Termogênese/genética
13.
Mol Cells ; 36(4): 376-84, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24046187

RESUMO

S-adenosyl methionine (SAM) is a key intermediate in the metabolism of sulfur amino acids and is a major methyl donor in the cell. Although the low plasma level of SAM has been associated with atherosclerosis, the effect of SAM administration on atherosclerosis is not known. Endothelial dysfunction is an early prerequisite for atherosclerosis. This study was undertaken to investigate the possible preventive effect of SAM on endothelial dysfunction and the molecular mechanism of its action. SAM treatment prevented endothelial dysfunction in high fat diet (HFD)-fed rats. In cultured human aortic endothelial cells, linoleic acid (LA) increased and SAM decreased cell apoptosis and endoplasmic reticulum stress. Both LA and SAM increased heme oxygenase-1 (HO-1) expression in an NF-E2-related factor 2-dependent manner. However, knockdown of HO-1 reversed only the SAM-induced preventive effect of cell apoptosis. The LA-induced HO-1 expression was dependent on PPARα, whereas SAM induced HO-1 in a PPAR-independent manner. These data demonstrate that SAM treatment prevents endothelial dysfunction in HFDfed animals by inducing HO-1 in vascular endothelial cells. In cultured endothelial cells, SAM-induced HO-1 was responsible for the observed prevention of cell apoptosis. We propose that SAM treatment may represent a new therapeutic strategy for atherosclerosis.


Assuntos
Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Heme Oxigenase-1/metabolismo , S-Adenosilmetionina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Células Cultivadas , Dieta Hiperlipídica , Células Endoteliais/enzimologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Indução Enzimática , Regulação Enzimológica da Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Ácido Linoleico/farmacologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico/efeitos dos fármacos
14.
World J Surg Oncol ; 10: 146, 2012 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-22799602

RESUMO

BACKGROUND: Clusterin is known to be expressed in many human neoplasms, and is believed to participate in the regeneration, migration, and anti-apoptosis of tumor cells. However, few reports have addressed the relationship between the manifestation of clusterin and clinicopathologic parameters in pancreas cancer patients. In the present study, the authors investigated the expression of clusterin and its clinical significance in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining was performed for clusterin in tumor tissues obtained from patients who received pancreatic resection with radical intent, and the associations of clusterin expression with various clinicopathologic parameters were analyzed in addition to the relation between its expression and survival. RESULTS: Immunoreactivity for clusterin was observed in 17 of the 52 (33%) pancreatic adenocarcinomas examined. In addition, clusterin positivity was found to be associated with preoperative serum carcinoembryonic antigen level, perineural invasion, and, most strongly, lymph node metastasis. The survival analysis identified tumor differentiation and lymph node metastasis as the only significant prognostic factors. CONCLUSION: Although not an independent prognostic factor, clusterin immunoreactivity can be used in conjunction with lymph node metastasis to predict survival in cases of pancreatic adenocarcinoma.


Assuntos
Adenocarcinoma Mucinoso/metabolismo , Clusterina/biossíntese , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pâncreas/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , República da Coreia/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida/tendências
15.
Exp Mol Med ; 44(9): 562-70, 2012 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-22809900

RESUMO

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are considered the key determinants of insulin resistance. Impaired mitochondrial function in obese animals was shown to induce the ER stress response, resulting in reduced adiponectin synthesis in adipocytes. The expression of inducible nitric oxide synthase (iNOS) is increased in adipose tissues in genetic and dietary models of obesity. In this study, we examined whether activation of iNOS is responsible for palmitate-induced mitochondrial dysfunction, ER stress, and decreased adiponectin synthesis in 3T3L1 adipocytes. As expected, palmitate increased the expression levels of iNOS and ER stress response markers, and decreased mitochondrial contents. Treatment with iNOS inhibitor increased adiponectin synthesis and reversed the palmitate-induced ER stress response. However, the iNOS inhibitor did not affect the palmitate-induced decrease in mitochondrial contents. Chemicals that inhibit mitochondrial function increased iNOS expression and the ER stress response, whereas measures that increase mitochondrial biogenesis (rosiglitazone and adenoviral overexpression of nuclear respiratory factor-1) reversed them. Inhibition of mitochondrial biogenesis prevented the rosiglitazone-induced decrease in iNOS expression and increase in adiponectin synthesis. These results suggest that palmitate-induced mitochondrial dysfunction is the primary event that leads to iNOS induction, ER stress, and decreased adiponectin synthesis in cultured adipocytes.


Assuntos
Adipócitos , Mitocôndrias/metabolismo , Óxido Nítrico Sintase Tipo II , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adiponectina/biossíntese , Tecido Adiposo/metabolismo , Animais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Resistência à Insulina/genética , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Renovação Mitocondrial/efeitos dos fármacos , Renovação Mitocondrial/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fator 1 Nuclear Respiratório , Obesidade/genética , Obesidade/metabolismo , Ácido Palmítico/farmacologia , Rosiglitazona , Tiazolidinedionas/farmacologia
16.
Blood ; 120(3): 691-6, 2012 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-22661699

RESUMO

Acute GVHD (aGVHD) remains a major source of morbidity after allogeneic hematopoietic cell transplantation. CD30 is a cell-surface protein expressed on certain activated T cells. We analyzed CD30 expression on peripheral blood T-cell subsets and soluble CD30 levels in 26 patients at the time of presentation of aGVHD, before the initiation of treatment, compared with 27 patients after hematopoietic cell transplantation without aGVHD (NONE). Analysis by flow cytometry showed that patients with aGVHD had a greater percentage of CD30 expressing CD8(+) T cells with the difference especially pronounced in the central memory subset (CD8(+)CD45RO(+)CD62L(+)): GVHD median 12.4% (range, 0.8%-33.4%) versus NONE 2.1% (0.7%, 17.5%), P < .001. There were similar levels of CD30 expression in naive T cells, CD4(+) T cells, and regulatory (CD4(+)CD127(low)CD25(+)) T cells. Plasma levels of soluble CD30 were significantly greater in patients with GVHD: median 61.7 ng/mL (range, 9.8-357.1 ng/mL) versus 17.4 (range, 3.7-142.4 ng/mL) in NONE (P < .001). Immunohistochemical analysis of affected intestinal tissue showed many CD30(+) infiltrating lymphocytes present. These results suggest that CD30 expression on CD8(+) T-cell subsets or plasma levels of soluble CD30 may be a potential biomarker for aGVHD. CD30 may also represent a target for novel therapeutic approaches for aGVHD.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Citometria de Fluxo/métodos , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Antígeno Ki-1/metabolismo , Linfócitos T Reguladores/metabolismo , Doença Aguda , Antígenos de Superfície/metabolismo , Biomarcadores/metabolismo , Biópsia , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/terapia , Neoplasias Hematológicas/terapia , Humanos , Memória Imunológica/imunologia , Intestinos/imunologia , Intestinos/patologia , Antígeno Ki-1/sangue , Antígeno Ki-1/imunologia , Solubilidade , Linfócitos T Reguladores/imunologia , Transplante Homólogo
17.
Biochem Biophys Res Commun ; 422(1): 200-5, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22575505

RESUMO

Tumor associated macrophages are known to be closely linked with tumor progression and metastasis. On the other hand, clusterin is overexpressed in several tumor types and regarded as a putative tumor-promoting factor due to this overexpression and the subsequent induction of chemoresistance. In our previous study, clusterin was found to induce the expression of matrix metalloproteinase-9 (MMP-9) in macrophages, and MMP-9 is known to be essential for tumor cell migration and invasion via basement membrane breakdown. Because paracrine interactions between tumor cells and surrounding macrophages regulate metastasis, these findings raise the possibility that clusterin promotes the secretion of cytokines in macrophages in addition to MMP-9. Here, we demonstrate that clusterin upregulates the expressions of chemotactic cytokines, that is, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1ß (MIP-1ß), regulated upon activation, normal T cell expressed and secreted (RANTES), and tumor necrosis factor-α (TNF-α) in Raw264.7 macrophages. In particular, clusterin stimulated TNF-α secretion via the activations of ERK, JNK, and PI3K/Akt pathways in a time and dose-dependent manner. Furthermore, clusterin-induced TNF-α secretion was found to play a critical role in the chemotactic migration of Raw264.7 macrophages. It was also found that clusterin acts directly as a chemoattractant for macrophages. Together, these results suggest that clusterin stimulates the expression and secretion of TNF-α, which plays a critical role in promoting macrophage chemotaxis, via ERK, JNK, and PI3K/Akt pathways. Collectively, these findings describe a novel function for clusterin as an inducer of TNF-α in macrophages and their chemotactic migration, and suggest that clusterin has a tumor-promoting effect.


Assuntos
Quimiotaxia/fisiologia , Clusterina/fisiologia , Macrófagos Peritoneais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Clusterina/farmacologia , MAP Quinase Quinase 4/biossíntese , Sistema de Sinalização das MAP Quinases , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/biossíntese , Proteínas Proto-Oncogênicas c-akt/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
18.
J Biol Chem ; 287(22): 18429-39, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22493506

RESUMO

The role of serine palmitoyltransferase (SPT) and de novo ceramide biosynthesis in cardiac ceramide and sphingomyelin metabolism is unclear. To determine whether the de novo synthetic pathways, rather than ceramide uptake from circulating lipoproteins, is important for heart ceramide levels, we created cardiomyocyte-specific deficiency of Sptlc2, a subunit of SPT. Heart-specific Sptlc2-deficient (hSptlc2 KO) mice had a >35% reduction in ceramide, which was limited to C18:0 and very long chain ceramides. Sphingomyelinase expression, and levels of sphingomyelin and diacylglycerol were unchanged. But surprisingly phospholipids and acyl CoAs contained increased saturated long chain fatty acids. hSptlc2 KO mice had decreased fractional shortening and thinning of the cardiac wall. While the genes regulating glucose and fatty acid metabolism were not changed, expression of cardiac failure markers and the genes involved in the formation of extracellular matrices were up-regulated in hSptlc2 KO hearts. In addition, ER-stress markers were up-regulated leading to increased apoptosis. These results suggest that Sptlc2-mediated de novo ceramide synthesis is an essential source of C18:0 and very long chain, but not of shorter chain, ceramides in the heart. Changes in heart lipids other than ceramide levels lead to cardiac toxicity.


Assuntos
Ceramidas/metabolismo , Coração/fisiopatologia , Miocárdio/enzimologia , Serina C-Palmitoiltransferase/metabolismo , Animais , Glicemia/metabolismo , Western Blotting , Células Cultivadas , Marcação In Situ das Extremidades Cortadas , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serina C-Palmitoiltransferase/genética
19.
J Am Soc Nephrol ; 23(1): 73-85, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22052058

RESUMO

Upregulation of clusterin occurs in several renal diseases and models of nephrotoxicity, but whether this promotes injury or is a protective reaction to injury is unknown. Here, in the mouse unilateral ureteral obstruction model, obstruction markedly increased the expression of clusterin, plasminogen activator inhibitor-1 (PAI-1), type I collagen, and fibronectin. Compared with wild-type mice, clusterin-deficient mice exhibited higher levels of PAI-1, type I collagen, and fibronectin and accelerated renal fibrosis in response to obstruction. In cultured rat tubular epithelium-like cells, adenovirus-mediated overexpression of clusterin inhibited the expression of TGF-ß-stimulated PAI-1, type I collagen, and fibronectin. Clusterin inhibited TGF-ß-stimulated Smad3 activity via inhibition of Smad3 phosphorylation and its nuclear translocation. Moreover, intrarenal delivery of adenovirus-expressing clusterin upregulated expression of clusterin in tubular epithelium-like cells and attenuated obstruction-induced renal fibrosis. In conclusion, clusterin attenuates renal fibrosis in obstructive nephropathy. These results suggest that upregulation of clusterin during renal injury is a protective response against the development of renal fibrosis.


Assuntos
Clusterina/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Adenoviridae , Animais , Caderinas/metabolismo , Colágeno Tipo I/metabolismo , Fibronectinas/metabolismo , Fibrose , Humanos , Rim/patologia , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Ratos Sprague-Dawley , Serpina E2/metabolismo , Obstrução Ureteral/complicações
20.
Mol Cells ; 32(6): 571-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22083307

RESUMO

Methionine and choline-deficient diet (MCD)-induced fatty liver is one of the best-studied animal models of fatty liver disease. The present study was performed to clarify the relative contributions of individual lipid metabolic pathways to the pathogenesis of MCD-induced fatty liver. Hepatic lipogenesis mediated by the sterol regulatory element-binding protein (SREBP-1c) was increased at 1 week, but not at 6 weeks, of MCD feeding. On the other hand, (14)C-palmitate oxidation did not change at 1 week, but significantly decreased at 6 weeks. This decrease was associated with increased expression of fatty acid translocase, a key enzyme involved in fatty acid uptake. Expression of endoplasmic reticulum stress markers was increased in mice given MCD for both 1 and 6 weeks. These findings suggest the presence of time-dependent differences in lipid metabolism in MCD-induced fatty liver disease: SREBP-1c-mediated lipogenesis is important in the early stages of fatty liver disease, whereas increased fatty acid uptake and decreased fatty acid oxidation become more important in the later stages.


Assuntos
Deficiência de Colina/complicações , Fígado Gorduroso/metabolismo , Mobilização Lipídica/genética , Metionina/deficiência , Animais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Estresse do Retículo Endoplasmático , Fator de Iniciação 2 em Eucariotos/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/etiologia , Fibrose , Expressão Gênica , Glicerol-3-Fosfato O-Aciltransferase/genética , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Fosforilação , Fatores de Transcrição de Fator Regulador X , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fator de Transcrição CHOP/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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