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1.
FEBS J ; 285(9): 1593-1610, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29493888

RESUMO

Tumor necrosis factor (TNF)-α activates a diverse array of signaling pathways in vascular endothelial cells (ECs), leading to the inflammatory phenotype that contributes to the vascular dysfunction and neutrophil emigration in patients with sepsis. To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF-α-stimulated ECs. This study investigated the role of dual specificity phosphatase-6 (DUSP6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP6 is important for TNF-α-induced endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta and in vein. Moreover, genetic deletion of Dusp6 in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF-α or lipopolysaccharide (LPS). The role of DUSP6 was further investigated in primary human umbilical vein endothelial cells (HUVECs). Employing RNAi approach in which endogenous DUSP6 was ablated, we showed a critical function of DUSP6 to facilitate TNF-α-induced ICAM-1 expression and endothelial leukocyte interaction. Interestingly, DUSP6-promoted endothelial inflammation is independent of extracellular signaling-regulated kinase (ERK) signaling. On the other hand, inducible DUSP6 leads to activation of canonical nuclear factor (NF)-κB-mediated transcription of ICAM-1 gene in TNF-α-stimulated human ECs. These results are the first to demonstrate a positive role of DUSP6 in endothelial inflammation-mediated pathological process and the underlying mechanism through which DUSP6 promotes NF-κB signaling in the inflamed ECs. Our findings suggest that manipulation of DUSP6 holds great potential for the treatment of acute inflammatory diseases.


Assuntos
Fosfatase 6 de Especificidade Dupla/fisiologia , Endotélio Vascular/enzimologia , Regulação da Expressão Gênica/fisiologia , Molécula 1 de Adesão Intercelular/biossíntese , Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/prevenção & controle , Transferência Adotiva , Animais , Aorta , Adesão Celular , Quimiotaxia de Leucócito , Fosfatase 6 de Especificidade Dupla/deficiência , Fosfatase 6 de Especificidade Dupla/genética , Endotélio Vascular/patologia , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Genes Reporter , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Molécula 1 de Adesão Intercelular/genética , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , Infiltração de Neutrófilos , Fator de Necrose Tumoral alfa/farmacologia , Células U937 , Veia Cava Inferior , Irradiação Corporal Total
2.
Environ Toxicol ; 33(3): 280-294, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29168595

RESUMO

Berberine, an isoquinoline alkaloid isolated from several traditional Chinese herbal medicines, has been shown to suppress growth and induce apoptosis in some tumor cell lines. However, berberine has also been reported to attenuate H2 O2 -induced oxidative injury and apoptosis. The basis for these ambiguous effects of berberine-triggering or preventing apoptosis-has not been well characterized to date. In the current investigation, we examined whether berberine exerts cytotoxic effects on mouse embryos at the blastocyst stage and affects subsequent embryonic development in vitro and in vivo. Treatment of blastocysts with berberine (2.5-10 µM) induced a significant increase in apoptosis and a corresponding decrease in trophectoderm cell number. Moreover, the implantation success rate of blastocysts pretreated with berberine was lower than that of their control counterparts. Pretreatment with berberine was also associated with increased resorption of postimplantation embryos and decreased fetal weight. In an animal model, intravenous injection of berberine (2, 4, or 6 mg/kg body weight/d) for 4 days resulted in apoptosis of blastocyst cells and early embryonic developmental injury. Berberine-induced injury of mouse blastocysts appeared to be attributable to oxidative stress-triggered intrinsic apoptotic signaling processes that impaired preimplantation and postimplantation embryonic development. Taken together, our results clearly demonstrate that berberine induces apoptosis and retards early preimplantation and postimplantation development of mouse embryos, both in vitro and in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Berberina/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Estresse Oxidativo , Animais , Blastocisto/citologia , Blastocisto/efeitos dos fármacos , Contagem de Células , Implantação do Embrião/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos ICR , Gravidez , Transdução de Sinais
3.
Clin Rheumatol ; 35(11): 2807-2813, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27585925

RESUMO

Recent studies have reported that osteoarthritis (OA) is related to inflammation and atherosclerosis. Studies on the relationship between OA and acute coronary syndrome (ACS) are scant. We evaluated the risk of ACS in OA patients of an Asian population. This longitudinal, population-based cohort study investigated the incidence and risk of ACS in 46,042 patients with newly diagnosed OA and 46,042 controls selected randomly from the general population and frequency matched according to age, sex, and entry year (2002-2003). The follow-up period ranged from the entry date until the date of an ACS event, loss to follow-up, or the end of 2010. We employed Cox proportional hazard models to estimate the effects of OA on the risk of ACS. The OA patients showed a 15 % higher risk of ACS than did the controls after adjustment for covariates (adjusted hazard ratio [aHR] = 1.15, 95 % confidence interval [CI] = 1.08-1.23). The risk of ACS in the OA patients was the greatest in young adults (aHR = 2.0, 95 % CI = 1.44-2.78), followed by middle-aged (aHR = 1.15, 95 % CI = 1.01-1.31) and older adults (aHR = 1.11, 95 % CI = 1.03-1.20). The risk of ACS was 1.96-fold in young adults with mild to moderate OA and 3.51-fold in young adults with severe OA compared with their counterparts without OA. OA carries an increased risk of ACS, particularly in young adults with severe OA. Clinicians should employ proactive strategies for preventing ACS occurrence in these patients.


Assuntos
Síndrome Coronariana Aguda/epidemiologia , Osteoartrite/epidemiologia , Adulto , Fatores Etários , Idoso , Comorbidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Fatores Sexuais , Taiwan/epidemiologia , Adulto Jovem
4.
Inflammation ; 39(2): 830-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26846884

RESUMO

Diabetes mellitus may cause vascular endothelial damage via endothelial matrix metalloproteinase-2 (MMP-2). The role of endothelial autophagy in MMP-2-mediated cell injury in response to high-glucose (HG) stimulation was rarely described. In this study, we used HG-treated human umbilical vein endothelial cells (HUVECs) to investigate the effect of autophagy on MMP-2-induced cell transmigration and apoptosis. THP-1 transmigration was detected by the transmigration assay. Light chain 3 (LC3, representing autophagy), MMP-2, and poly (ADP-ribose) polymerase (PARP, representing apoptosis) of HG (33 mM)-treated HUVECs were evaluated by western blot analysis. The MMP-2 activity was also examined by gelatin zymography. We used GM6001 (10 µM, an MMP-2 inhibitor) to investigate the relationship of MMP-2 and THP-1 transmigration. Using 3-methyladenine (3MA, 5 mM, an LC3 inhibitor), we explored the effects of autophagy on MMP-2 expression, THP-1 transmigration, and apoptosis. Our results showed that HG increased LC3-II expression, MMP-2 activity, THP-1 transmigration, and cleaved PARP expression in a time-dependent manner (0-48 h); among them, LC3-II appeared earlier (0-24 h) than the others (24-48 h). GM6001 suppressed MMP-2 activity and ameliorated THP-1 transmigration. 3MA suppressed LC3-II expression and increased MMP-2 expression, THP-1 transmigration, and cleaved PARP expression. From these sequential findings, we demonstrated that autophagy plays a protective role in MMP-2-mediated cell transmigration and cell death in HG-stimulated HUVECs.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Movimento Celular/fisiologia , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Adenina/análogos & derivados , Adenina/metabolismo , Linhagem Celular , Diabetes Mellitus/patologia , Dipeptídeos/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Glucose/metabolismo , Humanos , Inibidores de Metaloproteinases de Matriz/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo
5.
Medicine (Baltimore) ; 94(30): e1252, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26222866

RESUMO

Alzheimer dementia (AD) is the commonest form of dementia. Although illiteracy is associated with high prevalence of dementia of the Alzheimer type (DAT), their relationship is still unclear. Nevertheless, mild DAT in illiterate participants seems to be due to brain atrophy.In this study, we compared the impact of brain metabolism efficiency in healthy participants and less-educated patients with mild DAT using 2-fluoro-2-deoxy-D-glucose (F-FDG-PET) positron emission tomography. Out of 43 eligible less-educated participants with dementia, only 23 (14 women and 9 men) met Diagnostic and Statistical Manual (DSM)-III-R or DSM-IV criteria for DAT and AD and were included. Participants with intracranial insults were excluded by brain magnetic resonance imaging and participants with metabolic or systemic conditions were excluded by blood sampling. In addition, 16 cognitively normal elderly (age >70 years), including 7 women and 9 men, were enrolled in the sham group. The PET imaging data were analyzed using statistical parametric mapping (SPM8) to determine reliability and specificity.Glucose metabolic rate was low in the DAT group, especially in the middle temporal gyrus, middle frontal gyrus, superior frontal gyrus, inferior frontal gyrus, posterior cingulate gyrus, angular gyrus, parahippocampal gyrus, middle occipital gyrus, rectal gyrus, and lingual gyrus.Our results showed that DAT patients with less education not only have prominent clinical signs and symptoms related to dementia but also decreased gray matter metabolism.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Encefalopatias Metabólicas/diagnóstico por imagem , Encéfalo/metabolismo , Fluordesoxiglucose F18 , Glucose/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Encefalopatias Metabólicas/complicações , Encefalopatias Metabólicas/metabolismo , Feminino , Humanos , Masculino , Prognóstico , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
6.
Ann Biomed Eng ; 43(9): 2220-30, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25631203

RESUMO

Nicotine is the major component in cigarette smoke and has been recognized as a risk factor for various cardiovascular diseases such as atherosclerosis. However, the definite pathogenesis of nicotine-mediated endothelial dysfunction remains unclear because hemodynamic factor in most of prior in vitro studies was excluded. To understand how nicotine affects endothelium in the dynamic environment, human umbilical vein endothelial cells were treated by different laminar shear stresses (LSS; 0, 6, 8, and 12 dynes cm(-2)) with and without 10(-4) M nicotine for 12 h in a parallel plate flow system, following detections of cellular morphology and apoptotic level. Our results showed that cells sheared by 12 dynes cm(-2) LSS with nicotine excessively elongated and aligned with the flow direction, and exhibited significant apoptosis as compared to the groups with nicotine or LSS alone. We reasoned that the irregular morphological rearrangement and elevated apoptosis were resulted from the interruption of mechanostasis due to cytoskeletal collapse. Furthermore, all the impaired responses can be rescued by treatment with free radical scavenger ascorbic acid (10(-4) M), indicating oxidative stress was likely mediated with the impairments. In summary, our findings demonstrated an essential role of LSS in nicotine-mediated endothelial injury occurring in the physiological environment.


Assuntos
Apoptose/efeitos dos fármacos , Citoesqueleto/metabolismo , Hemodinâmica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Nicotina/farmacologia , Resistência ao Cisalhamento/efeitos dos fármacos , Humanos , Nicotina/efeitos adversos
7.
Public Health Nutr ; 18(10): 1839-46, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25482035

RESUMO

OBJECTIVE: The present study investigates the relationship between BMI and all-cause mortality among middle-aged and older adults with or without pre-existing diseases. DESIGN: A population-based cohort study. SETTING: The Taiwan Longitudinal Study on Aging is a nationwide prospective cohort study comprising a representative random sample of middle-aged and older adults. The study period was 1996-2007. SUBJECTS: We followed 4145 middle-aged and older adults, totalling 42,353 person-years. RESULTS: Overweight and mildly obese participants showed a 16% and 30% decrease in the risk of death, respectively, compared with those of normal weight after adjusting for potential covariates (e.g. demographic characteristics, health behaviour, co-morbidities and physical function). Underweight adults showed a 1.36-fold increased adjusted hazard ratio of death compared with normal-weight adults. Adults with a BMI of 27.0-28.0 kg/m(2) showed a significantly lower adjusted hazard ratio of all-cause mortality rate compared with adults who had normal BMI values when they had coexisting hypertension or diabetes (adjusted hazard ratio = 0.50; 95% CI 0.30, 0.81 for hypertension and adjusted hazard ratio=0.41; 95% CI 0.18, 0.89 for diabetes). CONCLUSIONS: The study demonstrates that underweight people have a higher risk of death, and overweight and mildly obese people have a lower risk of death, compared with people of normal weight among middle-aged and older adults. An optimal BMI may be based on the individual, who exhibits pre-existing diseases or not.


Assuntos
Índice de Massa Corporal , Causas de Morte , Obesidade/mortalidade , Magreza/mortalidade , Idoso , Diabetes Mellitus , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Sobrepeso/mortalidade , Estudos Prospectivos , Valores de Referência , Fatores de Risco , Taiwan/epidemiologia
9.
Eur J Clin Invest ; 44(11): 1025-33, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25207756

RESUMO

BACKGROUND: We conducted a nationwide population-based cohort study to investigate the effects of asthma on the risk of stroke development in an Asian population. MATERIALS AND METHODS: Newly diagnosed asthmatic patients aged ≥ 18 years were identified, and asthma-free controls were randomly selected from the general population and frequency matched according to age, sex and index year using records obtained from the National Health Insurance Research Database between 2000 and 2010. Both cohorts were followed up until the end of 2011 to measure the incidence of stroke. The risk of stroke was analysed using Cox proportional hazard regression models, including factors such as sex, age and comorbidities. RESULTS: We followed the asthmatic patients for 104 697 person-years and followed the nonasthmatic people for 426 729 person-years. The incidence density rate of stroke increased in all of the groups of asthmatic patients compared with that of the controls when stratified according to sex, age and comorbidities. The hazard ratio (HR) of stroke was 1·37-fold greater for the asthmatic cohort, compared with that for the nonasthmatic cohort, after adjusting for sex, age and comorbidities. The adjusted HR of developing stroke substantially increased with older age and the increased frequency of asthmatic exacerbation and hospitalization. The patients receiving beta-2 agonists as a treatment exhibited a significantly greater risk of stroke compared with the patients receiving only inhaled corticosteroids, after adjusting for covariates. CONCLUSION: Asthma may be an independent risk factor for stroke, and its severity exhibits a dose response of stroke development.


Assuntos
Asma/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Idoso , Asma/epidemiologia , Estudos de Casos e Controles , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Taiwan/epidemiologia , Adulto Jovem
10.
Langmuir ; 30(22): 6489-96, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24832682

RESUMO

In this work, the hemocompatibility of polyampholyte copolymers from the mixed-charge copolymerization of negatively charged 3-sulfopropyl methacrylate (SA) and positively charged [2-(methacryloyloxy)ethyl] trimethylammonium (TMA) was studied. Charge-bias variation of the prepared poly(SA-co-TMA) copolymers can be controlled using the regulated SA and TMA monomer ratio via homogeneous free radical copolymerization. A systematic study of how charge-bias variations in poly(SA-co-TMA) copolymers affect the hemocompatibility in human blood plasma was reported. The hydrodynamic size of prepared polymers and copolymers is determined to illustrate the correlations between intermolecular cationic/anionic associations and the blood compatibility of polySA, poly(SA-co-TMA), and polyTMA suspensions in human blood plasma. It was found that the protein resistance and hydration capability of prepared copolymers can be effectively controlled by regulating the charge balance of the SA/TMA compositions in poly(SA-co-TMA). The results suggest that polyampholyte copolymers of poly(SA-co-TMA) with overall charge neutrality have a high hydration capability and the best antifouling, anticoagulant, and antihemolytic activities as well as zwitterionic sulfobetaine-based homopolymers when in contact with blood plasma at human body temperature.


Assuntos
Materiais Biocompatíveis/química , Polímeros/química , Materiais Biocompatíveis/efeitos adversos , Humanos , Metacrilatos/química , Polímeros/efeitos adversos
11.
Chem Biol Interact ; 217: 1-8, 2014 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-24727557

RESUMO

WJ1376-1 and WJ1398-1 are new synthetic compounds developed based on the structure of the Chinese herbal medicine osthole. Previously, we reported that WJ1376-1 and WJ1398-1 can induce cell-cycle arrest by activating ATR kinase (ataxia telangiectasia and rad3 related kinase) and inhibiting the phosphorylation of Aurora A kinase. In this study, we determined that WJ1376-1 and WJ1398-1 strongly inhibited the migration and invasion in human colorectal cancer cells at concentrations as low as 1µM. In the transforming growth factor (TGF)-ß-induced epithelial-mesenchymal transition model, WJ1376-1 and WJ1398-1 potently downregulated the transcription factor Snail1, the mesenchymal protein vimentin, and matrix metalloprotease-9, but upregulated the epithelial protein E-cadherin. WJ1376-1 and WJ1398-1 also inhibited the TGF-ß-induced phosphorylation of Smad2 and of Akt at Ser 473, and the nuclear translocation of Smad2 was substantially lower in WJ1376-1- and WJ1398-1-treated cells than it was in control cells. In transient transfection experiments, we observed that WJ1376-1 and WJ1398-1 strongly inhibited TGF-ß-stimulated activity of a Smad reporter. Finally, WJ1376-1 and WJ1398-1 blocked TGF-ß-induced phosphorylation of the TGF-ß Type I receptor (TGF-ßRI). These results suggest that WJ1376-1 and WJ1398-1 inhibit cell migration and invasion by suppressing TGF-ßRI phosphorylation and subsequently hindering both Smad2 and phosphatidylinositol 3-kinase/Akt signaling pathways.


Assuntos
Adenocarcinoma/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Cumarínicos/farmacologia , Ácidos Hidroxâmicos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Smad2/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células HCT116 , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , RNA/química , RNA/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad2/genética , Fator de Crescimento Transformador beta/metabolismo
12.
Eur Respir J ; 43(3): 801-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23988762

RESUMO

Studies on the association between asthma and pulmonary thromboembolism are considerably limited. We investigated whether pulmonary embolism is associated with asthma using a nationwide cohort study. We identified 31,356 patients with newly diagnosed asthma in 2002-2008 and 125,157 individuals without asthma randomly selected from the general population, frequency matched by age, sex and index year using the National Health Insurance Research Database. Both cohorts were followed-up until the end of 2010 to measure the incidence of pulmonary embolism. Cox proportional hazards regression analysis was used to measure the hazard ratio of pulmonary embolism for the asthmatic cohort, compared with the nonasthmatic cohort. We followed 186,182 person-years for asthmatic patients and 743,374 person-years for nonasthmatic subjects. The hazard ratio of pulmonary embolism was 3.24 for the asthmatic cohort, compared with the nonasthmatic cohort after adjusting for sex, age, comorbidities and oestrogen supplementation. The risk of developing pulmonary embolism significantly increased with the increased frequency of asthma exacerbation and hospitalisation. This nationwide cohort study suggests that the risk of developing pulmonary embolism is significantly increased in asthmatic patients compared to the general population. Frequent asthma exacerbation and hospitalisation are significantly associated with pulmonary embolism risk.


Assuntos
Asma/complicações , Embolia Pulmonar/complicações , Adulto , Idoso , Asma/diagnóstico , Asma/epidemiologia , Estudos de Coortes , Comorbidade , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiologia , Fatores de Risco , Taiwan/epidemiologia , Resultado do Tratamento
13.
Langmuir ; 28(51): 17733-42, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23181727

RESUMO

In this work, the hemocompatibility of zwitterionic polypropylene (PP) fibrous membranes with varying grafting coverage of poly(sulfobetaine methacrylate) (PSBMA) via plasma-induced surface polymerization was studied. Charge neutrality of PSBMA-grafted layers on PP membrane surfaces was controlled by the low-pressure and atmospheric plasma treatment in this study. The effects of grafting composition, surface hydrophilicity, and hydration capability on blood compatibility of the membranes were determined. Protein adsorption onto the different PSBMA-grafted PP membranes from human fibrinogen solutions was measured by enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies. Blood platelet adhesion and plasma clotting time measurements from a recalcified platelet-rich plasma solution were used to determine if platelet activation depends on the charge bias of the grafted PSBMA layer. The charge bias of PSBMA layer deviated from the electrical balance of positively and negatively charged moieties can be well-controlled via atmospheric plasma-induced interfacial zwitterionization and was further tested with human whole blood. The optimized PSBMA surface graft layer in overall charge neutrality has a high hydration capability and keeps its original blood-inert property of antifouling, anticoagulant, and antithrmbogenic activities when it comes into contact with human blood. This work suggests that the hemocompatible nature of grafted PSBMA polymers by controlling grafting quality via atmospheric plasma treatment gives a great potential in the surface zwitterionization of hydrophobic membranes for use in human whole blood.


Assuntos
Betaína/análogos & derivados , Materiais Biocompatíveis/química , Membranas Artificiais , Plasma/química , Polipropilenos/química , Adsorção , Anticoagulantes/química , Anticoagulantes/farmacologia , Betaína/química , Materiais Biocompatíveis/farmacologia , Proteínas Sanguíneas/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Metacrilatos/química , Adesividade Plaquetária/efeitos dos fármacos , Propriedades de Superfície
14.
PLoS One ; 7(7): e40999, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848421

RESUMO

PKC plays a pivotal role in mediating monocyte adhesion; however, the underlying mechanisms of PKC-mediated cell adhesion are still unclear. In this study, we elucidated the signaling network of phorbol ester PMA-stimulated human monocyte adhesion. Our results with pharmacological inhibitors suggested the involvement of AMPK, Syk, Src and ERK in PKC-dependent adhesion of THP-1 monocytes to culture plates. Biochemical analysis further confirmed the ability of PMA to activate these kinases, as well as the involvement of AMPK-Syk-Src signaling in this event. Direct protein interaction between AMPK and Syk, which requires the kinase domain of AMPK and linker region of Syk, was observed following PMA stimulation. Notably, we identified Syk as a novel downstream target of AMPK; AICAR can induce Syk phosphorylation at Ser178 and activation of this kinase. However, activation of AMPK alone, either by stimulation with AICAR or by overexpression, is not sufficient to induce monocyte adhesion. Studies further demonstrated that PKC-mediated ERK signaling independent of AMPK activation is also involved in cell adhesion. Moreover, AMPK, Syk, Src and ERK signaling were also required for PMA to induce THP-1 cell adhesion to endothelial cells as well as to induce adhesion response of human primary monocytes. Taken together, we propose a bifurcated kinase signaling pathway involved in PMA-mediated adhesion of monocytes. PKC can activate LKB1/AMPK, leading to phosphorylation and activation of Syk, and subsequent activation of Src and FAK. In addition, PKC-dependent ERK activation induces a coordinated signal for cytoskeleton rearrangement and cell adhesion. For the first time we demonstrate Syk as a novel substrate target of AMPK, and shed new light on the role of AMPK in monocyte adhesion, in addition to its well identified functions in energy homeostasis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Monócitos/enzimologia , Proteína Quinase C/metabolismo , Proteínas Tirosina Quinases/metabolismo , Carcinógenos/farmacologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Linhagem Celular , Citoesqueleto/metabolismo , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monócitos/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinase Syk , Acetato de Tetradecanoilforbol/farmacologia , Quinases da Família src/metabolismo
15.
Cell Signal ; 24(11): 2166-78, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22841895

RESUMO

Endoplasmic reticulum (ER) stress is induced in infectious and inflammatory conditions, but its role in inflammatory responses still remains elusive. In this study we found tunicamycin (TM) and brefeldin A (BFA), two ER stressors, could attenuate lipopolysaccharide (LPS)-elicited inducible nitric oxide synthase (iNOS) gene expression in murine RAW264.7 macrophages, and this effect was not resulting from the effects on IKK or MAPKs activation. However, ER stressors could block NF-κB binding to the iNOS promoter in late-phase signaling evoked by LPS. Results indicated that inhibition of RelB nuclear translocation and p300 expression are involved in the anti-inflammatory actions of ER stressors. We also found that ER stressors could block LPS- and IFN (α, ß, and γ)-mediated STAT1 phosphorylation. Our results suggest that activation of MKP-1 via a Ca/calmodulin/calcineurin pathway accounts for the inhibitory effect of ER stressors on IFN signaling. MKP-1 was downregulated by IFN-γ and is a newly identified protein phosphatase targeting STAT1. Taken together, these results indicate that multiple mechanisms are involved in the inhibition of LPS-induced iNOS gene expression by ER stressors. These include downregulation of RelB and p300, upregulation of MKP-1, and inhibition of the JAK/STAT signaling pathway.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Animais , Antibacterianos/farmacologia , Brefeldina A/farmacologia , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Fosfatase 1 de Especificidade Dupla/metabolismo , Histonas/metabolismo , Interferon gama/farmacologia , Janus Quinases/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelB/metabolismo , Tunicamicina/farmacologia , Fatores de Transcrição de p300-CBP/metabolismo
16.
J Ethnopharmacol ; 142(1): 175-87, 2012 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-22543166

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The Ger-Gen-Chyn-Lian-Tang (GGCLT), an officially standardized mixture of Chinese herbal medicines, consists of Puerariae Radix, Scutellariae Radix, Coptidis Rhizoma and Glycyrrhizae Radix in a ratio of 8:3:3:2. In this study, we evaluated the benefits of GGCLT in atherosclerotic progression. METHODS: The major constituents of GGCLT were analyzed by HPLC. ApoE-/- mice taken 0.15% cholesterol diet were orally given vehicle or GGCLT (2 g/kg/day) for 12 weeks. Serum levels of lipid and glucose were analyzed, and atherosclerosis was examined by histological analyses. Cultures of vascular smooth muscle cells, hepatocytes and bone marrow-derived macrophages were used to investigate the action mechanisms of GGCLT. RESULTS: Our quantitation results indicated that GGCLT contains puerarin, daidzin, daidzein, baicalin, baicalein, wogonin, palmatine, coptisine, berberine and glycyrrhizin. GGCLT decreased serum levels of total cholesterol and LDL, but not TG and HDL in ApoE-/- mice. In parallel, GGCLT treatment reduced atherosclerotic lesions and collagen expression in atheroma plaques. In vascular smooth muscle cells, GGCLT could reduce cell migration, but failed to affect cell viability and proliferation. In hepatocytes, GGCLT can reduce lipid accumulation, and this action was accompanied by the activation of AMPK, upregulation of PPARs, and downregulation of FAS. Pharmacological approach indicated that the latter two events contributing to the anti-lipogenesis is resulting from AMPK pathway, and the lipid lowering effect of GGCLT in hepatocytes is mediated by AMPK and PPARα pathways. Meanwhile, two of the major components of GGCLT, berberine and puerarin, also activated AMPK and decreased lipid accumulation in hepatocytes with berberine of higher efficacy. Besides in hepatocytes, AMPK signaling was also activated by GGCLT in vascular smooth muscle cells and macrophages. CONCLUSIONS: These results demonstrate the anti-atherosclerotic action of Chinese medicine mixture GGCLT in ApoE-/- atherosclerotic mouse model. Mechanistic study suggests that activation of AMPK and PPARα in hepatocytes leading to a decrease of lipid formation contributes to the beneficial action of GGCLT in atherosclerosis treatment.


Assuntos
Aterosclerose/tratamento farmacológico , Cardiotônicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta Torácica/citologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Cardiotônicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Medicamentos de Ervas Chinesas/farmacologia , Glycyrrhiza , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Wistar , Scutellaria baicalensis
17.
Int J Infect Dis ; 16(6): e464-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22497965

RESUMO

OBJECTIVES: Although the application of cardiac implantable electronic devices (CIED) has greatly increased over the past few decades, CIED endocarditis is becoming a challenging scenario in clinical practice. Recently, Staphylococcus lugdunensis has emerged as a pathogen in CIED endocarditis. However, a detailed phenotypic characterization has not been addressed. METHODS: We conducted a systematic literature review covering the period between 1989 and 2011 using the PubMed, Medline, Cochrane, and Embase databases. All cases included had a CIED in use and met the modified Duke criteria for infective endocarditis, and all had isolates of S. lugdunensis. The clinical features, predisposing conditions, echocardiographic findings, and therapeutic strategies/outcomes were evaluated. Polymorphonuclear neutrophil functions were examined to test whether the defect of innate immunity may play a permissive role in host susceptibility to tissue destruction in S. lugdunensis endocarditis. RESULTS: Eleven patients with CIED endocarditis caused by S. lugdunensis were identified. Their mean age was 61.7±11.2 years, and there was a male preponderance (72.7%). Six patients (54.5%) had undergone re-manipulation of the pacing system within a few months to years before the occurrence of clinical symptoms. The median time of symptoms before the diagnosis of CIED endocarditis was 60 days. On echocardiography, vegetations in the CIED were detected in nine cases (81.8%). Nine patients (81.8%) underwent surgical removal of the entire device, and one patient received medical treatment alone. The overall mortality rate was 18.2%. One patient had a septic perforation of the ventricular septum, with a high serum level of N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) in the absence of pump failure. The assessment of polymorphonuclear neutrophil (PMN) functions revealed normal PMN responses to the various stimuli and normal oxidative burst responses. CONCLUSIONS: Identification and differentiation of staphylococcal species in a timely manner would allow us to intervene more aggressively at an earlier stage to prevent unfavorable outcomes. Clinicians should never consider the isolation of S. lugdunensis as contamination. In selected individuals, therapeutic abstention may be preferable to exposing patients to a high risk of S. lugdunensis CIED endocarditis due to re-manipulation of the pacing system. The prognostic value of NT-pro-BNP warrants further investigations.


Assuntos
Endocardite Bacteriana/microbiologia , Marca-Passo Artificial/efeitos adversos , Infecções Relacionadas à Prótese/microbiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus lugdunensis/isolamento & purificação , Idoso , Remoção de Dispositivo , Ecocardiografia/métodos , Endocardite Bacteriana/sangue , Endocardite Bacteriana/diagnóstico por imagem , Feminino , Humanos , Peptídeo Natriurético Encefálico/sangue , Neutrófilos/imunologia , Fragmentos de Peptídeos/sangue , Infecções Relacionadas à Prótese/sangue , Infecções Relacionadas à Prótese/diagnóstico por imagem , Reoperação , Fatores de Risco , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/diagnóstico por imagem , Fatores de Tempo , Ultrassonografia Doppler em Cores
18.
Am J Emerg Med ; 30(8): 1661.e5-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22033392

RESUMO

The management of life-threatening complications in HIV-associated immune reconstitution syndrome is becoming a challenging scenario in emergency practice, especially in the era of highly active antiretroviral therapy paralleled by increased worldwide incidence of HIV infection. Here, we described a 37-year-old woman with acute hypoxic respiratory failure, acute renal failure, and hypercalcemic crisis as the presenting features of HIV-associated immune reconstitution syndrome. In this patient, the restored granulomatous host response toward isolated pulmonary Mycobacterium avium complex infection led to a near-fatal catastrophe. This report reinforces the importance of introducing a rapid, systematic approach of hypercalcemia at the emergency department and the need for clinicians to maintain awareness of this distinct manifestation.


Assuntos
Infecções por HIV/complicações , Síndrome Inflamatória da Reconstituição Imune/etiologia , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Hipercalcemia/etiologia , Hipercalcemia/terapia , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare/complicações
19.
Am J Emerg Med ; 30(8): 1665.e5-7, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22100475

RESUMO

Severe hypercalcemia in the course of renal failure is quite unusual. If unrecognized, irreversible inexorable attrition of renal function takes place, carrying a substantial morbidity and mortality. In particular, acute nonobstructive pyelonephritis is barely considered in the primary differential diagnosis of renal failure. Without urinary obstruction, kidney hypoperfusion, or exposure to nephrotoxic agents, a significant decline in glomerular filtration rate generally does not occur. We report a case with severe hypercalcemia after acute renal failure caused by fulminating bacterial pyelonephritis. To obviate unnecessary intervention, preserve organ function, and achieve better outcomes, clinicians should not miss this entity.


Assuntos
Lesão Renal Aguda/complicações , Hipercalcemia/etiologia , Pielonefrite/complicações , Serviço Hospitalar de Emergência , Infecções por Escherichia coli/complicações , Feminino , Humanos , Hipercalcemia/diagnóstico , Pessoa de Meia-Idade
20.
Circ Res ; 109(12): 1375-86, 2011 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-22021929

RESUMO

RATIONALE: Hypoxia is a significant perturbation that exacerbates endothelial barrier dysfunction, contributing to the disruption of vascular homeostasis and the development of various diseases such as atherosclerosis and metastasis of tumors. To date, it is not known what strategy might be used to counter the effect of hypoxia on endothelial permeability. OBJECTIVE: This study investigated the role of nitrite in regulating vascular integrity under hypoxic conditions. METHODS AND RESULTS: We found denitrosylation and the resulting activation of caspase-3 to be critical for hypoxia-induced endothelial permeability. Nitrite treatment led to S-nitrosylation and the inactivation of caspase-3, suppressing the barrier dysfunction of endothelia caused by hypoxia. This process required the conversion of nitrite to bioactive nitric oxide in a nitrite reductase-dependent manner. Using primary human umbilical vein endothelial cells as a model, we showed that in the presence of nitrite, the S-nitrosylated and inactivated form of caspase-3 was unable to cleave ß-catenin, a key component in the VE-cadherin complex. Therefore, nitrite treatment led to the maintenance of VE-cadherin-mediated adherens junctions under hypoxic conditions. In in vivo experiments using a zebrafish model, nitrite was found to protect blood vessels from hypoxia-induced vascular leakage. CONCLUSIONS: These results are the first to demonstrate that nitrite plays a critical role in the protection of endothelial barrier function against hypoxic insult. Our findings show that nitrite holds great potential for the treatment of diseases associated with hypoxia-induced disorder of vascular homeostasis.


Assuntos
Caspase 3/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/fisiologia , Endotélio Vascular/fisiopatologia , Hipóxia/fisiopatologia , Nitritos/farmacologia , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/fisiologia , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Bovinos , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Hipóxia/complicações , Camundongos , Modelos Animais , Óxido Nítrico/metabolismo , Peixe-Zebra , beta Catenina/metabolismo
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