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1.
BMC Gastroenterol ; 20(1): 217, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32650722

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease is characterized by excessive hepatic fat accumulation. Some individuals frequently present elevated gamma-glutamyl transferase (GGT) levels without fatty liver ultrasound images and other abnormal liver enzymes levels. However, whether these individuals are at an elevated risk for developing fatty liver is unclear. We compared fatty liver change rates and risk factors between individuals with frequently elevated GGT levels and those with normal levels. METHODS: We designed a retrospective cohort study on the basis of complete medical checkup records. One group of individuals had presented normal serum GGT levels during the observation period (Normal-GGT group, n = 2713). Another group had had abnormal elevated serum GGT levels frequently (Abnormal-GGT group, n = 264). We determined the fatty liver change incident rates before and after propensity score matching. We explored confounding factors affecting fatty changes in each group using univariate and multivariate Cox models. RESULTS: The change incidence rates were 5.80/1000 and 10.02/1000 person-years in the Normal-GGT and Abnormal-GGT groups, respectively. After propensity score matching, the incidence rates were 3.08/1000 and 10.18/1000 person-years in the Normal-GGT and Abnormal-GGT groups, respectively (p = 0.026). The factors associated with fatty liver changes in the Normal-GGT group included body mass index (BMI), hemoglobin, alanine aminotransferase (ALT), albumin, triglyceride (TG), fasting blood sugar, and high-density lipoprotein levels. Those in the Abnormal-GGT group were platelet counts and TG. In our multivariable analysis, BMI, ALT, albumin, and TG levels were independent predictors of fatty changes in the Normal-GGT group, and high TG level was the only independent predictor in the Abnormal-GGT group. CONCLUSIONS: The incidence rate of fatty liver change in the Abnormal-GGT group was higher than that in the Normal-GGT group. Consecutive elevated GGT levels increase the risk for fatty liver, and high TG levels in those individuals further independently increase the risk.


Assuntos
Hepatopatia Gordurosa não Alcoólica , gama-Glutamiltransferase , Alanina Transaminase , Humanos , Testes de Função Hepática , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos Retrospectivos
2.
Am J Physiol Gastrointest Liver Physiol ; 301(2): G230-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21636531

RESUMO

Human esophageal epithelium is continuously exposed to physical stimuli or to gastric acid that sometimes causes inflammation of the mucosa. Transient receptor potential vanilloid 1 (TRPV1) is a nociceptive, Ca(2+)-selective ion channel activated by capsaicin, heat, and protons. It has been reported that activation of TRPV1 expressed in esophageal mucosa is involved in gastroesophageal reflux disease (GERD) or in nonerosive GERD symptoms. In this study, we examined the expression and function of TRPV1 in the human esophageal epithelial cell line Het1A, focusing in particular on the role of oxidative stress. Interleukin-8 (IL-8) secreted by Het1A cells upon stimulation by capsaicin or acid with/without 4-hydroxy-2-nonenal (HNE) was measured by ELISA. Following capsaicin stimulation, the intracellular production of reactive oxygen species (ROS) was determined using a redox-sensitive fluorogenic probe, and ROS- and HNE-modified proteins were determined by Western blotting using biotinylated cysteine and anti-HNE antibody, respectively. HNE modification of TRPV1 proteins was further investigated by immunoprecipitation after treatment with synthetic HNE. Capsaicin and acid induced IL-8 production in Het1A cells, and this production was diminished by antagonists of TRPV1. Capsaicin also significantly increased the production of intracellular ROS and ROS- or HNE-modified proteins in Het1A cells. Moreover, IL-8 production in capsaicin-stimulated Het1A cells was enhanced by synthetic HNE treatment. Immunoprecipitation studies revealed that TRPV1 was modified by HNE in synthetic HNE-stimulated Het1A cells. We concluded that TRPV1 functions in chemokine production in esophageal epithelial cells, and this function may be regulated by ROS via posttranslational modification of TRPV1.


Assuntos
Canais de Cálcio/metabolismo , Células Epiteliais/metabolismo , Esôfago/metabolismo , Interleucina-8/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Canais de Cátion TRPV/metabolismo , Ácidos/farmacologia , Aldeídos/farmacologia , Animais , Canais de Cálcio/efeitos dos fármacos , Capsaicina/farmacologia , Linhagem Celular , Esôfago/citologia , Humanos , Interleucina-8/efeitos dos fármacos , Masculino , Mucosa/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Ratos , Ratos Wistar , Canais de Cátion TRPV/efeitos dos fármacos
3.
Int J Hyperthermia ; 26(2): 101-7, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20146564

RESUMO

Previously we have demonstrated that whole body hyperthermia (WBH) improves insulin resistance in diabetic mice. The aim of the present study was to perform a gene expression analysis of the liver and adipose tissue of obesity-induced insulin resistant diabetic mice (db/db mice) after WBH and to define the molecules that play the important role in improvement of insulin resistance by WBH. Male db/db mice were treated with WBH 3 times per week for 12 weeks. Total RNA was extracted from the liver and adipose tissue of db/db mice, and differences in the gene expression profiles among db/+ mice, untreated db/db mice, and WBH-treated db/db mice were investigated using a high-density DNA microarray. WBH directly targets liver and adipose tissue, resulting in modifications in NF-kappaB and IL-6 signalling pathways, as well as lipid metabolism. Although the mechanisms have not yet been completely investigated, we can conclude that WBH may provide a new therapeutic or preventive modality against type 2 diabetes mellitus and metabolic or insulin resistance syndrome through the modification of several signalling pathways.


Assuntos
Diabetes Mellitus Experimental/genética , Hipertermia Induzida , Tecido Adiposo/fisiologia , Animais , Análise por Conglomerados , Diabetes Mellitus Experimental/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Resistência à Insulina/genética , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Transdução de Sinais/fisiologia
4.
Nihon Shokakibyo Gakkai Zasshi ; 106(4): 554-9, 2009 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-19346725

RESUMO

A 58-year-old man was brought to our hospital with left upper abdominal pain which suddenly appeared on the previous evening. An abdominal CT scan showed localized retention of ascites, a slightly high density mass under the left upper abdominal wall, with a high density area detected within the mass, which was suggestive of leakage of contrast medium from peripheral branches of the omental artery. From these findings intraperitoneal hemorrhage caused by bleeding from the greater omentum was suspected. Angiographic examination of the abdomen indicated extravasation of contrast medium from blood vessels of the right gastroepiploic artery. Transarterial embolization was carried out and permanent hemostasis was achieved. Injury, anticoagulant, neoplasms, varix, torsion of the omentum, and segmental arterial mediolysis (SAM) etc have been reported as causes of omental bleeding, but none of these were found in our case. We diagnosed the present case as idiopathic omental bleeding.


Assuntos
Embolização Terapêutica/métodos , Hemorragia/terapia , Omento/irrigação sanguínea , Artéria Gastroepiploica , Humanos , Masculino , Pessoa de Meia-Idade
5.
J Pharmacol Sci ; 106(3): 469-77, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18360096

RESUMO

Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and anti-inflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects.


Assuntos
Alanina/análogos & derivados , Antiulcerosos/farmacologia , Aspirina/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Proteínas de Membrana/análise , Fosfoproteínas/análise , Quinolonas/farmacologia , Alanina/farmacologia , Animais , Linhagem Celular , Citoproteção , Imunofluorescência , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley , Proteína da Zônula de Oclusão-1
6.
Dig Dis Sci ; 53(7): 1785-91, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17990109

RESUMO

Ménétrier's disease has been reported to be associated with Helicobacter pylori infection. The aim of this study was to investigate the genetic characteristics of various virulence factors and cytokine expression profiles in Helicobacter pylori isolated from patients with Ménétrier's disease. The genotyping of virulence factors was accomplished by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Induction of various cytokines in MKN45 cells or gastric fibroblasts by Helicobacter pylori stimulus was measured by real-time reverse transcription-PCR. We found that the Helicobacter pylori strain isolated from a patient with Ménétrier's disease was different from other strains in the MseI-RFLP pattern of the ureC gene. Helicobacter pylori isolated from a patient with Ménétrier's disease showed the highest hepatocyte growth factor (HGF) and TNF-alpha mRNA expressions from gastric fibroblasts, and the highest TNF-alpha expression from MKN45 cells. The results in this study suggest that the difference in cytokine production, depending on the difference in bacteria components, plays an important role in the development of Ménétrier's disease.


Assuntos
Fibroblastos/metabolismo , Gastrite Hipertrófica/genética , Gastrite Hipertrófica/microbiologia , Infecções por Helicobacter/complicações , Helicobacter pylori/genética , Helicobacter pylori/patogenicidade , Fator de Crescimento de Hepatócito/metabolismo , Gastropatias/genética , Gastropatias/microbiologia , Citocinas/metabolismo , Gastrite Hipertrófica/metabolismo , Genótipo , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Gastropatias/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Virulência
7.
Int J Hyperthermia ; 23(3): 217-24, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17523016

RESUMO

BACKGROUND AND AIM: The activation of NF-kappaB induces production of inflammatory cytokines and up regulation of endothelial cell adhesion molecules (ECAM). ECAM (e.g., E-selectin, VCAM-1 and ICAM-1) associates to the recruitment of leukocytes into tissue exposed to inflammatory situation. In this study, we investigated the effects of hyperthermia on the activation of NF-kappaB and the up regulation of E-selectin and VCAM-1 in human endothelial cells stimulated by TNF-alpha. METHODS: Human arterial endothelial cells (HAEC) were pretreated with hyperthermia for 60 min at 42 degrees C, followed by incubation at 37 degrees C in a passively cooled incubator, before TNF-alpha stimulation. To assess the effects of hyperthermia on TNF-alpha-induced up regulation of ECAM and TNF-alpha-induced activation of NF-kappaB, we measured ECAM by ELISA, and evaluated the activation of NF-kappaB by Western blotting after TNF-alpha stimulation. The accumulation of HO-1, Hsp70 and IkappaBalpha in hyperthermia-treated HAEC was also assessed by Western blotting. To investigate the role of Hsp70, we treated HAEC with geranylgeranylacetone (GGA, Hsp70 inducer) 2 h before hyperthermia, and then measured ECAM in TNF-alpha-stimulated HAEC by ELISA. RESULTS: Pretreatment of hyperthermia reduced TNF-alpha-induced up regulation of E-selectin and VCAM-1. In addition, accumulation of Hsp70, HO-1 and IkappaBalpha protein were up-regulated after hyperthermia. Furthermore, Western blotting analysis revealed that pretreatment of hyperthermia attenuated TNF-alpha-induced translocation of p65 into the nuclei of HAEC. Moreover, GGA enhanced Hsp70 accumulation induced by hyperthermia. Hyperthermia pretreatment combined with GGA induced further inhibition of TNF-alpha-induced up regulation of ECAM when compared with hyperthermia alone. CONCLUSION: Pretreatment of hyperthermia blocks TNF-alpha-induced NF-kappaB activation, resulting in the inhibition of ECAM up regulation in HAEC.


Assuntos
Selectina E/metabolismo , Endotélio Vascular/metabolismo , Febre/fisiopatologia , NF-kappa B/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Artérias/citologia , Artérias/efeitos dos fármacos , Artérias/metabolismo , Células Cultivadas , Diterpenos/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Proteínas I-kappa B/metabolismo , Inibidor de NF-kappaB alfa , Fator de Transcrição RelA/metabolismo , Regulação para Cima/fisiologia
8.
Int J Hyperthermia ; 23(3): 259-65, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17523018

RESUMO

AIM: In this study, we examined the efficacy of whole body hyperthermia (WBH) on obesity-induced insulin resistance in diabetic mice. METHODS: Male db/db mice were treated with WBH 3 times per week for 12 weeks. The rectal temperature of mice reached 38.0 degrees C 5 min after heating, and was kept at 38.0 degrees C for 30 min. At the end of each week, tail snip glucose levels were determined under fasting conditions. The GLUT-4 gene expression of muscle tissue was analyzed by real-time PCR. RESULTS: (1) WBH-treated db/db mice showed a significant decrease in fasting blood glucose level as compared with untreated db/db mice (p < 0.01). (2) Plasma insulin levels in untreated db/db mice at the age of 10 weeks were significantly increased compared with those of db/+ mice (p < 0.0001). On the other hand, the reduction (31%) in insulin levels in WBH-treated mice indicated improved insulin sensitivity. (3) The ability of WBH to increase insulin sensitivity was further established in glucose tolerance tests and insulin tolerance tests. (4) Urine albumin of db/db mice significantly increased compared with those of db/+ mice at 18 weeks of age (p < 0.001). This increase in urinary albumin was significantly inhibited by WBH (p < 0.01). (5) WBH up-regulated the expression of GLUT4 mRNA in skeletal muscle. CONCLUSION: Although the mechanisms have not yet been completely investigated, WBH may provide a new therapeutic or preventive modality against obesity-related diseases such as T2DM and metabolic or insulin resistance syndrome.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Hipertermia Induzida , Resistência à Insulina/fisiologia , Obesidade/fisiopatologia , Albuminúria/fisiopatologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/terapia , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/sangue , Regulação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Músculo Esquelético/metabolismo , Obesidade/terapia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/sangue
9.
Eur J Pharmacol ; 546(1-3): 11-8, 2006 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-16919261

RESUMO

Oxidized low-density lipoprotein (ox-LDL) plays an important in the development of atherosclerosis by stimulating the production of reactive oxygen species in endothelial cells, and thereby up-regulating vascular cell adhesion molecule-1 (VCAM-1). The objectives of the present study were to determine the effects of azelnidipine, a new calcium channel blocker, on the expression of VCAM-1 induced by 7-ketocholesterol, components of ox-LDL, and tumor necrosis factor-alpha (TNF-alpha). The scavenging activities of azelnidipine against superoxide, hydroxyl, and carbon-centered radicals were determined by electron spin resonance assay. The levels of intracellular reactive oxygen species were determined fluorometrically with the use of dichlorodihydrofluorescein diacetate (H(2)DCF-DA). Human aortic endothelial cells and U937 were used as endothelial cells and monocytic cells, respectively. The surface expression and mRNA levels of VCAM-1 were determined by enzyme immunoassay and RT-PCR performed on endothelial cell monolayers stimulated with 7-ketocholesterol or TNF-alpha. The numbers of monocytic cells adhering on the stimulated endothelial cells were counted in the microscopic fields. Translocation of p65 protein to the nucleus was estimated by fluorescence microscopy. Azelnidipine, but not nifedipine, reduced the signal intensity of 1,1-diphenyl-2-picrylhydrazyl radicals. Azelnidipine scavenged hydroxyl radicals, but not superoxide radicals. Intracellular levels of reactive oxygen species and RelA (p65) nuclear translocation in stimulated endothelial cells were reduced by azelnidipine. Azelnidipine significantly inhibited the expression of protein and mRNA of VCAM-1, and prevented the U937 cell adhesion to endothelial cells treated with 7-ketocholesterol or TNF-alpha. These results suggest that azelnidipine works as an anti-atherogenic agent by inhibiting the reactive oxygen species-dependent expression of VCAM-1 induced by 7-ketocholesterol and TNF-alpha.


Assuntos
Aorta/efeitos dos fármacos , Ácido Azetidinocarboxílico/análogos & derivados , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/farmacologia , Células Endoteliais/efeitos dos fármacos , Sequestradores de Radicais Livres/farmacologia , Inflamação/prevenção & controle , Espécies Reativas de Oxigênio/metabolismo , Aorta/citologia , Aorta/metabolismo , Ácido Azetidinocarboxílico/farmacologia , Ácido Azetidinocarboxílico/uso terapêutico , Compostos de Bifenilo , Bloqueadores dos Canais de Cálcio/uso terapêutico , Adesão Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Óxidos N-Cíclicos , Di-Hidropiridinas/uso terapêutico , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Fluoresceínas , Sequestradores de Radicais Livres/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas , Indicadores e Reagentes , Inflamação/metabolismo , Cetocolesteróis/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Nifedipino/farmacologia , Picratos , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/metabolismo , Fatores de Tempo , Fator de Necrose Tumoral alfa/farmacologia , Células U937 , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
Biofactors ; 28(1): 1-7, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17264388

RESUMO

Helicobacter pylori (H. pylori) infection, the main cause of chronic gastritis, increases gastric cancer risk. The infection causes inflammatory cells to produce reactive oxygen metabolites that may damage DNA and promote carcinogenesis. However, its precise role in gastric carcinogenesis is as yet unknown. Recently we reported that H. pylori water extract (HPE) has an initiating activity on two-stage mouse skin carcinogenesis. In this study, we investigated the effects of anti-oxidants, ascorbic acid and a combination of superoxide dismutase (CuZnSOD)and catalase, on two-stage mouse skin carcinogenesis. Ascorbic acid and CuZnSOD/catalase were given to mice during the period of HPE-initiation. Both the ascorbic acid and CuZnSOD/catalase treatment attenuated the incidence of tumor formation. The present results suggest that HPE induces tumor formation via reactive oxygen species (ROS) production.


Assuntos
Helicobacter pylori , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/microbiologia , Animais , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Fracionamento Celular , Feminino , Camundongos , Camundongos Endogâmicos SENCAR , Mutação , Neoplasias Cutâneas/metabolismo , Superóxido Dismutase/farmacologia
11.
Cancer Lett ; 229(2): 223-33, 2005 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-16095811

RESUMO

The transcription factor NF-kappaB is reportedly activated by anti-cancer chemotherapeutic compounds in many cancer cell lines and NF-kappaB activation is one mechanism by which tumors become resistant to apoptosis. Antioxidants have been reported to serve as potent NF-kB inhibitors. In this study, we investigated the ability of edaravone to enhance apoptosis induced by CPT-11 through inhibition of NF-kB. In vitro, SN38, the active metabolite of CPT-11, induced activation of NF-kB, the production of intracellular reactive oxygen species, the activation of caspase-3, and apoptosis in colon26 cells. Pretreatment with edaravone scavenged the SN38-produced reactive oxygen species, and inhibited the SN38-induced activation of NF-kB. Moreover, edaravone enhanced the activation of caspase-3, and the level of apoptosis induced by SN38. In vivo, the combination of edaravone with CPT-11 reduced subcutaneous tumor growth and number of pulmonary metastases more effectively than CPT-11 alone. These results demonstrate that the combination of edaravone with CPT-11 may constitute a new strategy for treating primary and metastatic colon cancer.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antipirina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , NF-kappa B/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Animais , Antineoplásicos/metabolismo , Antipirina/administração & dosagem , Apoptose/efeitos dos fármacos , Western Blotting , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/metabolismo , Caspase 3 , Caspases/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Edaravone , Ensaio de Desvio de Mobilidade Eletroforética , Sequestradores de Radicais Livres/administração & dosagem , Marcação In Situ das Extremidades Cortadas , Irinotecano , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Camundongos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio
12.
Atherosclerosis ; 180(1): 19-25, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15823271

RESUMO

The migration of circulating monocytes into the subendothelial space occurs through the expressing of some adhesion molecules on endothelial cells. In the present study, using human aortic endothelial cells (HAECs), we investigated whether a model compound for oxysterols, 25-hydroxycholesterol, can enhance the monocyte adherence to HAECs exposed to 25-hydroxycholesterol via increasing expression of vascular cell adhesion molecule-1 (VCAM-1). We also aimed to determine the in vitro effects of tocotrienols on the enhanced interaction between monocytes and endothelial cells. We found that 25-hydroxycholesterol enhances surface expression determined by ELISA, induces VCAM-1 mRNA expression by real time-PCR, and stimulates adhesiveness of HAECs to U937 monocytic cells in a dose-dependent fashion. The combination treatment with anti-VCAM-1 and anti-CD11b monoclonal antibodies significantly reduced the monocyte adherence to 25-hydroxycholesterol-stimulated HAECs. Compared to alpha-tocopherol, tocotrienols displayed a more profound inhibitory effect on adhesion molecule expression and monocytic cell adherence. We observed that delta-tocotrienol exerted a most profound inhibitory action on monocytic cell adherence when compared to alpha-tocopherol and alpha-, beta-, and gamma-tocotrienols. Tocotrienols accumulated in HAECs to levels approximately 25-95-fold greater than that of alpha-tocopherol. In conclusion, these results indicate that a model compound 25-hydroxycholesterol can enhance the interaction between monocytes and HAECs, and that tocotrienols had a profound inhibitory effect on monocytic cell adherence to HAECs relative to alpha-tocopherol via inhibiting the VCAM-1 expression. These superior inhibitory effects of tocotrienols may be dependent on their intracellular accumulation.


Assuntos
Antioxidantes/farmacologia , Endotélio Vascular/citologia , Hidroxicolesteróis/farmacologia , Monócitos/citologia , Tocotrienóis/farmacologia , Molécula 1 de Adesão de Célula Vascular/genética , Anticorpos Monoclonais/farmacologia , Aorta/citologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/imunologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Expressão Gênica/efeitos dos fármacos , Humanos , Monócitos/imunologia , RNA Mensageiro/análise , Células U937 , alfa-Tocoferol/farmacologia
13.
Eur J Med Chem ; 40(1): 69-74, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15642411

RESUMO

Six new galactoglycerolipid analogs, in which one or two 4-methylpentanoyl or trans-2-butenoyl groups are linked to the 2-O-beta-D-galactosylglycerol skeleton, were tested for their anti-tumor-promoting activity using a short-term in vitro assay for Epstein-Barr virus early antigen (EBV-EA) activation. All these compounds were more active than their linear or saturated reference compounds in inhibiting the EBV activation promoted by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), the diester 1-O-(4-methylpentanoyl)-2-O-[6-O-(4-methylpentanoyl)-beta-D-galactopyranosyl]-sn-glycerol resulting the most active glycoglycerolipid analog till now tested. Four compounds (three butenoates and one 4-methylpentanoate), when tested in the in vivo two-stage carcinogenesis test, exhibited also inhibitory effects on mouse skin tumor promotion.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Galactolipídeos/química , Carga Tumoral/efeitos dos fármacos , Animais , Antígenos Virais/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Galactolipídeos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos ICR , Mimetismo Molecular , Papiloma/tratamento farmacológico , Papiloma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Relação Estrutura-Atividade
14.
Redox Rep ; 9(6): 354-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15720832

RESUMO

The objectives were to determine the effects of alacepril, an angiotensin-converting enzyme inhibitor, on the expression of adhesion molecules and monocyte adherence to endothelial cells induced by 7-ketocholesterol (7-KC) and tumor necrosis factor (TNF)-alpha. We used human aortic endothelial cells (HAECs) and U937 monocytic cells. Surface expression and mRNA levels of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were determined by EIA and RT-PCR. Adherence of U937 to HAECs was assessed by adhesion assay. Incubation of HAEC with 7-KC increased the surface expression of protein and mRNA levels of ICAM-1 and VCAM-1 on HAECs and the production of reactive oxygen species (ROS) in HAECs. Pretreatment with alacepril reduced the enhanced expression of these molecules in a dose-dependent manner. The inhibitory effect of alacepril against 7-KC or TNF-alpha-induced CAMs expression was stronger than that of captopril or enalapril. Alacepril inhibited the production of ROS in HAECs stimulated by 7-KC or TNF-alpha. These results suggest that alacepril works as anti-atherogenic agent through inhibiting endothelial-dependent adhesive interactions with monocytes induced by 7-KC and TNF-alpha.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/análogos & derivados , Captopril/farmacologia , Adesão Celular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Inflamação/induzido quimicamente , Cetocolesteróis/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Relação Dose-Resposta a Droga , Enalapril/farmacologia , Endotélio Vascular/citologia , Inflamação/tratamento farmacológico , Molécula 1 de Adesão Intercelular/biossíntese , Monócitos/citologia , Espécies Reativas de Oxigênio/metabolismo , Molécula 1 de Adesão de Célula Vascular/biossíntese
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