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INTRODUCTION: Sepsis patients require timely and appropriate treatment in an intensive care setting. However, "do-not-attempt resuscitation" (DNAR) status may affect physicians' priorities and treatment preferences. The aim of this study was to evaluate whether DNAR status affects the outcomes of septic patients. METHODS: This was a retrospective cohort study included septic patients admitted to the emergency department intensive care unit (ED-ICU) in a university-based teaching hospital during April-November 2015. Septic patients admitted to the ED-ICU were included. RESULTS: Of the 132 eligible patients, 49.2% (65/132) had DNAR status (median age 80â¯years old, IQR, 73-86). The overall in-hospital mortality rate was 28.8% (38/132). Non-survivors had a higher percentage of receiving inotropes/vasopressors (52.6% vs 34.0%, pâ¯=â¯0.048), higher median Charlson comorbidity index scores [8.5 (IQR, 7-11.75) vs 8 (IQR, 6-9), pâ¯=â¯0.012], higher APACHE II score [25 (IQR, 20-30.25) vs 20 (IQR, 17-25), pâ¯=â¯0.002], and higher SOFA score [7 (IQR, 6-11) vs 6 (IQR,4-8), pâ¯=â¯0.012]. There was no significant difference in intubation among the two groups. In a multivariate logistic regression analysis, DNAR status was an independent predictor of in-hospital mortality (odds ratioâ¯=â¯6.22, 95% confidence interval (CI)â¯=â¯(2.71-17.88), pâ¯<â¯0.001). The area under the ROC curve for the logistic regression model was 0.84 [95% CIâ¯=â¯(0.77-0.92), pâ¯<â¯0.001]. In subgroup analysis, DNAR status remained an independent predictor of mortality among age ≥65â¯years and ≥80â¯years. CONCLUSION: After adjusting for comorbidities, treatments, and illness severity, DNAR status was associated with in-hospital mortality of septic patients. Further studies should evaluate physicians' attitudes toward septic patients with DNAR status.
Assuntos
Mortalidade Hospitalar , Ordens quanto à Conduta (Ética Médica) , Sepse/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Serviço Hospitalar de Emergência , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Appropriate utilization of intensive care unit (ICU) beds are essential. Patients with critical illness who have do not resuscitate (DNR) have a reduced priority of intensive care. However, the possibility of recovery/survival is ambiguous and multifactorial. OBJECTIVE: To deliberate the characteristics and outcomes of critical illness in patients with prior DNR who were admitted to the emergency department (ED)-ICU. METHOD: This was a retrospective cohort study conducted between April 2015 and November 2015 in a university-based hospital. Non-traumatic patients with DNR admitted to ED-ICU from ED were included. RESULTS: Seventy-eight non-trauma patients with prior DNR status were included in the final analysis. 51.3% (40/78) patients were male with median age 83 (IQR: 75-89) years. The median APACHE II score was 24.5 (IQR: 20-30). 50% (39/78) of the DNR patients survived to discharge. Patients who survived to discharge had lower APACHE II score (23 (IQR: 20-28) vs. 28 (18-38), p = 0.028). There was no significant difference in age, gender, and Charlson index. ROC curves were constructed, generating a cut-off of the APACHE II score at 29.5 for determining survival to discharge (AUC = 0.644, p = 0.028). In multivariate Cox proportional model, APACHE II score above 29.5 was an independent predictor for mortality. (Hazard ratio = 2.46; 95% confidence interval: 1.04-5.83, p = 0.042). CONCLUSION: Our study found that 50% of patients with prior DNR on ICU admission survived to discharge, indicating that aggressive care is not definitely futile. Further prospective studies are required to evaluate the cost-effectiveness and patients' and/or families' satisfaction of the ICU admission of DNR patients.
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Estado Terminal/mortalidade , Hospitalização/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Ordens quanto à Conduta (Ética Médica) , APACHE , Idoso , Idoso de 80 Anos ou mais , Serviço Hospitalar de Emergência/organização & administração , Feminino , Hospitais Universitários , Humanos , Unidades de Terapia Intensiva/organização & administração , Masculino , Análise Multivariada , Estudos Retrospectivos , Análise de Sobrevida , Taiwan/epidemiologiaRESUMO
Glioblastoma multiforme is the most common brain tumor in adults. Because of its highly invasive nature, it is not easy to treat, resulting in high mortality rates. Stromal interacting molecule 1 (Stim1) plays important roles in regulating store-operated Ca2+ entry, and controls invasion by cancer cells. However, the mechanisms and functions of Stim1 in glioma progression are still unclear. In this study, we investigated the effects of targeting Stim1 expression on glioma cell invasion. By analyzing profiles of glioblastoma multiforme patients from RNA-sequencing data in The Cancer Genome Atlas, higher expression levels of STIM1 were correlated with the poor survival. Furthermore, signaling pathways associated with tumor malignancy, including the epithelial-to-mesenchymal transition (EMT), were activated in patients with high STIM1 expression according to gene set enrichment analyses. Higher Stim1 levels were found in glioma cells compared to human astrocytes, and these higher levels enhanced glioma cell invasion. Xanthohumol (XN), a prenylated flavonoid extracted from the hop plant Humulus lupulus L. (Cannabaceae), significantly reduced cell invasion through inhibiting Stim1 expression. From an micro(mi)RNA array analysis, miR-4725-3p was up-regulated by XN treatment. Over-expression of miR-4725-3p inhibited glioma cell invasion via directly targeting the 3'-untranslated region of STIM1. The extracellular signal-regulated kinase/c-Fos pathway was also validated to participate in XN-up-regulated miR-4725-3p expression according to promoter and chromatin immunoprecipitation assays. These results emphasize that miR-4725-3p-inhibited STIM1 signaling is involved in XN-attenuated glioma cell invasion. These findings may provide insights into novel therapeutic strategies for future glioblastoma therapy and drug development. Open Data: Materials are available on https://cos.io/our-services/open-science-badges/ https://osf.io/93n6m/.
Assuntos
Antineoplásicos/farmacologia , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/patologia , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , Propiofenonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Interação Estromal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Colágeno , Combinação de Medicamentos , Feminino , Humanos , Laminina , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Mutagênese/efeitos dos fármacos , Mutagênese/genética , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Proteoglicanas , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/metabolismo , Molécula 1 de Interação Estromal/genéticaRESUMO
This study demonstrates the bioefficacy and gives mechanistic insights into a plant galactolipid 1,2-di-O-linolenoyl-3-O-ß-galactopyranosyl-sn-glycerol (dLGG) against metastatic melanoma using a syngeneic mouse model implanted with B16COX-2/Luc melanoma. dLGG-20 (p.o. dLGG 20 mg/kg) and anti-cancer drug CP-2 (i.p. cisplatin 2 mg/kg) treatment significantly inhibited lung metastasis of melanoma in mice 91 and 57%, respectively, as determined by bioluminescence intensity. Moreover, dLGG-20 and CP-2 treatment prolonged mouse mean survival time. dLGG-20 treatment significantly inhibited the expression levels of several molecular markers, that is, PCNA, MMP2, COX-2, VEGF, vimentin, snail, TGF-ß, ß-catenin, TNF-α, PD-1 and PD-L1 in mouse lung tissues compared to tumor control mice. Significant inhibition of macrophage and neutrophil infiltration and promotion of CD8 + Tc cell recruitment in the lung microenvironment was observed in dLGG-20-treated mice. A LC/MS-based comparative oxylipin metabolomics study showed that dLGG-20 treatment significantly induced (5.0- to 12.8-fold) the 12/15-LOX catalyzed oxylipin products in mouse serum including 17-HDHA from DHA, 15-HEPE from EPA, 8- and 12-HETEs from AA, and CYP450-derived 20-HETE from AA. CP-2 treatment increased 12/15-LOX derived 8-, 11- and 12-HETEs from AA, and CYP450 derived 11,12-EET from AA ad 9,10-DHOME from LA by 5.3- to 8.1-fold. Of note, dLGG and 17-HDHA were more effective than CP in preventing B16 melanoma cell-induced pulmonary vascular permeability in mice through inhibition of TNF-α production, up-regulation of tight junction proteins claudin1 and ZO-2 and deregulation of Src activation. In conclusion, this study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Permeabilidade Capilar/fisiologia , Glucosídeos/farmacologia , Glicerol/análogos & derivados , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Melanoma Experimental/secundário , Oxilipinas/sangue , Plantas/química , Artéria Pulmonar/fisiologia , Veias Pulmonares/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Transição Epitelial-Mesenquimal , Quinase 2 de Adesão Focal/metabolismo , Glicerol/farmacologia , Humanos , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Invasividade Neoplásica/prevenção & controle , Transdução de Sinais , Junções Íntimas/efeitos dos fármacos , Microambiente Tumoral , Fator de Necrose Tumoral alfa/fisiologia , Quinases da Família src/metabolismoRESUMO
BACKGROUND: Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and -resistant glioma cells and the possible mechanisms. METHODS: TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ. RESULTS: Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ-induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells. CONCLUSIONS: Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lignanas/farmacologia , Temozolomida/farmacologia , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Glioma , HumanosRESUMO
INTRODUCTION: RDW is a prognostic biomarker and associated with mortality in cardiovascular disease, stroke and metabolic syndrome. For elderly patients, malnutrition and multiple comorbidities exist, which could affect the discrimination ability of RDW in sepsis. The main purpose of our study was to evaluate the prognostic value of RDW in sepsis among elderly patients. METHODS: This was a retrospective cohort study conducted in emergency department intensive care units (ED-ICU) between April 2015 and November 2015. Elderly patients (≥65years old) who were admitted to the ED-ICU with a diagnosis of severe sepsis and/or septic shock were included. The demographic data, biochemistry data, qSOFA, and APACHE II score were compared between survivors and nonsurvivors. RESULTS: A total of 117 patients was included with mean age 81.5±8.3years old. The mean APACHE II score was 21.9±7.1. In the multivariate Cox proportional hazards model, RDW level was an independent variable for mortality (hazard ratio: 1.18 [1.03-1.35] for each 1% increase in RDW, p=0.019), after adjusting for CCI, any diagnosed malignancy, and eGFR. The AUC of RDW in predicting mortality was 0.63 (95% confidence interval [CI]: 0.52-0.74, p=0.025). In subgroup analysis, for qSOFA <2, nonsurvivors had higher RDW levels than survivors (17.0±3.3 vs. 15.3±1.4%, p=0.044). CONCLUSIONS: In our study, RDW was an independent predictor of in-hospital mortality in elderly patients with sepsis. For qSOFA scores <2, higher RDW levels were associated with poor prognosis. RDW could be a potential parameter used alongside the clinical prediction rules.
Assuntos
Unidades de Terapia Intensiva , Sepse/sangue , Idoso , Idoso de 80 Anos ou mais , Contagem de Eritrócitos , Índices de Eritrócitos , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Humanos , Masculino , Prognóstico , Curva ROC , Estudos Retrospectivos , Sepse/mortalidade , Taxa de Sobrevida/tendências , Taiwan/epidemiologiaRESUMO
BACKGROUND: Exercise preconditioning (EP(+) ) has been widely accepted as a being of safe and effective preventive measure for stroke. The purpose of this study was to investigate whether EP(+) improves outcomes of ischaemic stroke by promoting neuronal and glial expression of heat shock protein (HSP) 20. MATERIALS AND METHODS: Adult male Sprague-Dawley rats (288 in number) were used to investigate the contribution of HSP20-containing neurons and HSP20-containing glial cells in the exercise-mediated neuroprotection in the stroke condition using middle cerebral artery occlusion. RESULTS: Exercise preconditioning, in addition to increasing the numbers of both the HSP20-containg neurons (88 ± 8 vs. 43 ± 4; n = 8 each group; P < 0·05) and the HSP20-containg astrocytes (102 ± 10 vs. 56 ± 5; n = 8; P < 0·05) significantly attenuated stroke-induced brain infarct (140 ± 9 vs. 341 ± 20 mm(3) ; n = 8 per group; P < 0·01), neuronal apoptosis (20 ± 5 vs. 87 ± 7; n = 8 per group; n = 8; P < 0·01), glial apoptosis (29 ± 5 vs. 101 ± 4; n = 8; P < 0·01), and neurological deficits (6·6 ± 0·3 vs. 11·7 ± 0·8; n = 8 per group; P < 0·01). Reducing the numbers of both HSP20-containing neurons and HSP20-contaiing glia by intracerebral injection of pSUPER small interfering RNAί expressing HSP20 significantly reversed the beneficial effects of EP(+) in attenuating stroke-induced cerebral infarct, neuronal and glial apoptosis, and neurological deficits. CONCLUSIONS: The numbers of both the HSP20-containing neurons and the HSP20-containing glia inversely correlated with the outcomes of ischaemic stroke. In addition, preischaemic treadmill exercise improves outcomes of ischaemic stroke by increasing the numbers of both the HSP20-containing neurons and the HSP20-containing glia.
Assuntos
Proteínas de Choque Térmico HSP20/fisiologia , Condicionamento Físico Animal/fisiologia , Acidente Vascular Cerebral/prevenção & controle , Animais , Apoptose/fisiologia , Astrócitos/metabolismo , Astrócitos/fisiologia , Infarto Encefálico/fisiopatologia , Lobo Frontal/metabolismo , Proteínas de Choque Térmico HSP20/metabolismo , Ligadura , Masculino , Artéria Cerebral Média , Neuroglia/metabolismo , Neuroglia/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologiaRESUMO
The heat shock protein 72 (HSP 72) is a universal marker of stress protein whose expression can be induced by physical exercise. Here we report that, in a localized model of spinal cord injury (SCI), exercised rats (given pre-SCI exercise) had significantly higher levels of neuronal and astroglial HSP 72, a lower functional deficit, fewer spinal cord contusions, and fewer apoptotic cells than did non-exercised rats. pSUPER plasmid expressing HSP 72 small interfering RNA (SiRNA-HSP 72) was injected into the injured spinal cords. In addition to reducing neuronal and astroglial HSP 72, the (SiRNA-HSP 72) significantly attenuated the beneficial effects of exercise preconditioning in reducing functional deficits as well as spinal cord contusion and apoptosis. Because exercise preconditioning induces increased neuronal and astroglial levels of HSP 72 in the gray matter of normal spinal cord tissue, exercise preconditioning promoted functional recovery in rats after SCI by upregulating neuronal and astroglial HSP 72 in the gray matter of the injured spinal cord. We reveal an important function of neuronal and astroglial HSP 72 in protecting neuronal and astroglial apoptosis in the injured spinal cord. We conclude that HSP 72-mediated exercise preconditioning is a promising strategy for facilitating functional recovery from SCI.
Assuntos
Proteínas de Choque Térmico HSP72/análise , Proteínas de Choque Térmico HSP72/genética , Condicionamento Físico Animal , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/prevenção & controle , Medula Espinal/patologia , Regulação para Cima , Animais , Apoptose , Astrócitos/metabolismo , Astrócitos/patologia , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologiaRESUMO
Current conventional cancer therapies for melanoma brain metastasis (MBM) remain ineffective. In this study, we demonstrated the bioefficacy of a phyto-glyceroglycolipid, 1,2-di-O-α-linolenoyl-3-O-ß-galactopyranosyl-sn-glycerol (dLGG) alone, or in combination with liposomal doxorubicin (Lip-DOX) or Avastin against MBM in a syngeneic B16BM4COX-2/Luc brain-seeking melanoma mouse model. Treatment with dLGG-10, dLGG-25, dLGG-10 + Avastin-5, Lipo-DOX-2, dLGG-10 + Lipo-DOX-2 or Lipo-DOX-2 + Avastin-5 suppressed, respectively, 17.9%, 59.1%, 55.7%, 16.2%, 44.5% and 72.4% of MBM in mice relative to the untreated tumor control. Metastatic PD-L1+ melanoma cells, infiltration of M2-like macrophages and CD31+ endothelial cells, and high expression levels of 15-LOX/CYP450 4A enzymes in the brain tumor microenvironment of the tumor control mice were significantly attenuated in dLGG-treated mice; conversely, M1-like resident microglia and cytotoxic T cells were increased. A lipidomics study showed that dLGG promoted B16BM4 cells to secrete oxylipins 9,10-/12,13-EpOMEs into the culture medium. Furthermore, the conditioned medium of B16BM4 cells pretreated with dLGG or 9,10-EpOMEs + 12,13-EpOMEs drove M2-like macrophages to polarize into M1-like macrophages in vitro. An ex vivo 3D-culture assay further demonstrated that dLGG, 9,10-EpOME or 9,10-EpOME + 12,13-EpOME pretreatment attenuated B16BM4 cells invading brain tissue, and prevented microglia/macrophages infiltrating into the interface of melanoma plug and brain organ/tissue. In summary, this report provides a novel therapeutic strategy and mechanistic insights into phytogalactolipid dLGG for combating MBM.
RESUMO
Obesity leads to insulin resistance because the larger adipocytes in obese persons secrete proinflammatory cytokines that cause chronic inflammation in adipose tissue. This, in turn, leads to the alteration of adipokine secretion, which can induce insulin resistance. However, the development of insulin resistance without obesity is still obscure. We aimed to use an animal inflammation model with cotton pellet granuloma (CPG) in adipose tissue to characterize insulin resistance formation. We found that CPG in epididymal white adipose tissue (WAT), rather than in interscapular brown adipose tissue, impaired insulin sensitivity, and glucose utilization, and that it decreased levels of phosphoinsulin receptor and phospho-Akt in both muscle and liver tissue, but that it did not modify the body weight or food intake in mice. Macrophage infiltration in adipose tissue, leukocyte counts, monocyte chemoattractant protein-1, and interleukin-6 were elevated in CPG-treated mice. However, we found a marked decrease of plasma adiponectin only in the WAT group, which might have been because of the lower level of peroxisome proliferator-activated receptor-gamma in WAT. These results show that granuloma formation in WAT by implantation of a cotton pellet may induce insulin resistance under nonobese condition through circulating inflammatory mediators, especially the low level of adiponectin.
Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Granuloma/fisiopatologia , Resistência à Insulina , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/patologia , Animais , Glicemia/análise , Quimiocinas/metabolismo , Fibra de Algodão , Modelos Animais de Doenças , Epididimo/patologia , Teste de Tolerância a Glucose , Granuloma/etiologia , Granuloma/patologia , Hipoglicemiantes/farmacologia , Contagem de Leucócitos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/metabolismo , Infiltração de Neutrófilos/fisiologia , Obesidade , PPAR gama/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo , Tolbutamida/farmacologiaRESUMO
Bone morphogenetic protein-7 (BMP-7) protects kidneys from diabetic nephropathy (DN), and high glucose (HG)-induced oxidative stress is involved in DN. We investigated the antioxidative ability of BMP-7 using HG-treated mesangial cells. We treated rat mesangial cells (RMCs) with recombinant human BMP-7 (rhBMP-7) and examined changes in reactive oxygen species (ROS) levels and intracellular signals in response to HG-induced oxidative stress. rhBMP-7 decreased the level of ROS in HG-treated RMCs. In contrast, lowering endogenous BMP-7 by siRNA or BMP receptor II (BMP-RII) by anti-BMP-RII antibodies increased the level of ROS in HG-treated RMCs. rhBMP-7 increased Smad-1,5,8 phosphorylation, decreased PKCzeta and c-Jun N-terminal kinase (JNK) phosphorylation, and decreased fibronectin and collagen IV synthesis in HG-treated RMCs. In conclusion, we found that BMP-7 could protect mesangial cells from HG-induced oxidative stress by activating BMP-RII. The antioxidative activity of BMP-7 was primarily due to inhibition of PKCzeta, JNK phosphorylation, and c-jun activation.
Assuntos
Proteína Morfogenética Óssea 7/fisiologia , Citoproteção , Glucose/metabolismo , Hiperglicemia/metabolismo , Células Mesangiais/metabolismo , Estresse Oxidativo , Animais , Proteína Morfogenética Óssea 7/genética , Proteína Morfogenética Óssea 7/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Linhagem Celular , Glucose/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , MAP Quinase Quinase 4/metabolismo , Células Mesangiais/efeitos dos fármacos , Estresse Oxidativo/genética , Fosforilação , Proteína Quinase C/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/farmacologiaRESUMO
Role of muscarinic receptor in the regulation of glucose uptake or lipolysis in adipose tissue remained unclear. In epididymal white adipose tissue (WAT) isolated from Wistar rats, we observed that acetylcholine (ACh) attenuated the insulin-stimulated glucose uptake and the release of glycerol from WAT in a concentration-dependent manner. Using the blockade of specific antagonists, both actions of ACh were characterized mainly due to an activation of M3 receptors. In the presence of various inhibitors for PLC-PKC pathway, ACh-decreased glucose uptake was also reversed. Taken together, these results suggest that muscarinic M3 receptor is involved in the regulation of glucose uptake and/or lipolysis in adipose tissue.
Assuntos
Acetilcolina/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Glucose/metabolismo , Lipólise/fisiologia , Receptor Muscarínico M3/metabolismo , Acetilcolina/farmacologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Inibidores Enzimáticos/farmacologia , Glicerol/metabolismo , Insulina/metabolismo , Antagonistas da Insulina/metabolismo , Antagonistas da Insulina/farmacologia , Lipólise/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptor Muscarínico M3/efeitos dos fármacos , Fosfolipases Tipo C/antagonistas & inibidores , Fosfolipases Tipo C/metabolismoRESUMO
The role of hyperglycaemia in the pathogenesis of hypotension in diabetic disorders was investigated using the changes in cardiac M(2)-muscarinic receptor (M(2)-mAChR) gene expression in type-1-like diabetic rats and cultured cardiomyocytes. Blood pressure was markedly decreased in diabetic rats following the intravenous injection of streptozotocin (STZ) for 8 weeks. Also, the baroreflex sensitivity (Delta HR/Delta BP), as measured by the changes in heart rate (Delta HR) and mean blood pressure (Delta BP) 1 min after the intravenous injection of phenylephrine (10 microg/kg), was significantly increased. Arecaidine propargyl ester (APE), a M(2)-mAChR agonist produced a marked reduction in heart rate in these diabetic rats. Normalization of plasma glucose in diabetic rats using insulin (0.5 IU) or phlorizin (1 mg/kg) injection attenuated the blood pressure reduction and reversed the mRNA and protein levels of cardiac M(2)-mAChR. A high concentration of glucose (20 mmol/l) directly influenced the increase in gene expression of M(2)-mAChR in the H9c2 cardiac cell line. Hyperglycaemia induced an increase in cardiac M(2)-mAChR gene expression, suggesting a role in the pathogenesis of hypotension in diabetic disorders.
Assuntos
Diabetes Mellitus Tipo 1/patologia , Hiperglicemia/patologia , Hipotensão/patologia , Animais , Arecolina/análogos & derivados , Arecolina/farmacologia , Barorreflexo , Linhagem Celular , Agonistas Colinérgicos/farmacologia , Diabetes Mellitus Experimental , Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Hiperglicemia/complicações , Hipotensão/etiologia , Insulina/uso terapêutico , Masculino , Fenilefrina , Florizina/uso terapêutico , RNA Mensageiro/análise , Ratos , Ratos Wistar , Receptor Muscarínico M2/análise , Receptor Muscarínico M2/genética , Receptor Muscarínico M2/metabolismoRESUMO
Sinomenine, one of the alkaloids extracted from roots or stems of Sinomenium acutum, is documented to show antinociceptive action but the action mechanism is still unclear. The present study was aimed to investigate the effect of sinomenine on opioid mu-receptor (OMR). In Chinese Hamster Ovary (CHO) cell transfected with OMR, the binding of [(3)H]naloxone was displaced by sinomenine in a concentration-dependent manner. This compound also raised the phosphorylation of OMR in these cells. In a tail-flick test, sinomenine produced dose-dependent antinociception in mice, which was dose-dependently inhibited by pretreatment of naloxonazine, a selective OMR antagonist. Long-term pretreatment with sinomenine may delay the analgesic tolerance of morphine. The obtained results suggest that sinomenine has an ability to activate OMR, implicating the potential of sinomenine to be applied in clinic.
Assuntos
Analgésicos Opioides/farmacologia , Morfinanos/farmacologia , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Interações Medicamentosas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Morfinanos/química , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Receptores Opioides mu/genética , TransfecçãoRESUMO
Changes of cardiac M2-muscarinic receptor (M2-mAChR) gene expression was investigated in type-1 like diabetic rats induced by intravenous injection of streptozotocin (STZ) and type-2 like diabetic rats induced by fed with fructose-rich chow. Systolic blood pressure (SBP) in STZ-diabetic rats was significantly lower than that in age-matched non-diabetic rats, while the SBP in type-2 like diabetic rats was higher than in non-diabetic rats. Also, the mRNA or protein level of cardiac M2-mAChR in STZ-diabetic rats was markedly higher than non-diabetic rats, but it was not observed in type-2 like diabetic rats as compared to age-matched non-diabetic rats. Arecaidine propargyl ester (APE), the agonist of M2-mAChR, produced a marked reduction of heart rate in STZ-diabetic rats but made less influence on heart rate in fructose-fed rats or non-diabetic rats. The results suggest that cardiac M2-mAChR gene expression is raised in type-1 like diabetic rats but not in type-2 like diabetic rats, this difference mainly due to hyperglycemia, for the production of hypotension in diabetic disorders.
Assuntos
Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica/fisiologia , Miocárdio/metabolismo , Receptor Muscarínico M2/metabolismo , Animais , Arecolina/análogos & derivados , Arecolina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 2/etiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Frutose/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor Muscarínico M2/genética , EstreptozocinaRESUMO
In the present study, we investigated the mechanism(s) for glucose-lowering action of andrographolide in streptozotocin-induced diabetic rats (STZ-diabetic rats). Andrographolide lowered plasma glucose concentrations in a dose-dependent manner and increased plasma beta-endorphin-like immunoreactivity (BER) dose-dependently in diabetic rats. Both of these responses to andrographolide were abolished by the pretreatment of animals with prazosin or N-(2-(2-cyclopropylmethoxy) ethyl) 5-choro-alpha-dimethyl-1H-indole-3-thylamine (RS17053) at doses sufficient to block alpha1-adrenoceptors (ARs). Also, andrographolide enhanced BER release from isolated rat adrenal medulla in a concentration-related manner that could be abolished by alpha1-ARs antagonists. Bilateral adrenalectomy in STZ-diabetic rats eliminated the activities of andrographolide, including the plasma glucose-lowering effect and the plasma BER-elevating effect. Andrographolide failed to lower plasma glucose in the presence of opioid micro-receptor antagonists and in the opioid micro-receptor knockout diabetic mice. Treatment of STZ-diabetic rats with andrographolide resulted in the reduced expression of phosphoenolpyruvate carboxykinase (PEPCK) in liver and an increased expression of the glucose transporter subtype 4 (GLUT 4) in soleus muscle. These effects were also blocked by opioid micro-receptor antagonists. In conclusion, our results suggest that andrographolide may activate alpha1-ARs to enhance the secretion of beta-endorphin which can stimulate the opioid micro-receptors to reduce hepatic gluconeogenesis and to enhance the glucose uptake in soleus muscle, resulting in a decrease of plasma glucose in STZ-diabetic rats. However, the roles of other endogenous opioid peptides or the mixture of several opioid peptides in the activation of opioid micro-receptors associated with the plasma glucose-lowering action of andrographolide, should be considered and need more investigation in the future.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diterpenos/farmacologia , Hipoglicemiantes/farmacologia , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diterpenos/administração & dosagem , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/genética , Hipoglicemiantes/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Wistar , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Estreptozocina , beta-Endorfina/efeitos dos fármacos , beta-Endorfina/metabolismoRESUMO
A 29-year-old woman who was pregnant for 12 weeks presented with headache for one week and drowsiness for two days. Computed tomography of the brain revealed multifocal hematomas with mass effect. Decompressive craniectomy was done to relieve the increased intracranial pressure. Magnetic resonance angiography and cerebral angiography were subsequently performed, both demonstrating thrombosis of the left transverse sinus. Treatment of sinus thrombosis generally includes correction of increased intracranial pressure and administration of anticoagulants, such as heparin. However, in this case heparin was contraindicated for the presence of intracranial bleeding, a clinical dilemma that requires careful considerations to balance treatment risks and benefits.
Assuntos
Hemorragia Cerebral/complicações , Complicações na Gravidez/terapia , Trombose dos Seios Intracranianos/complicações , Adulto , Hemorragia Cerebral/terapia , Feminino , Humanos , Pressão Intracraniana , Gravidez , Trombose dos Seios Intracranianos/terapiaRESUMO
OBJECT: Insulin-like growth factor-I (IGF-I) has been shown to be a potent neurotrophic factor that promotes the growth of projection neurons, dendritic arborization, and synaptogenesis. Its neuroprotective roles may be coordinated by activation of Akt, inhibition of glycogen synthase kinase-3beta (GSK-3beta), and thus inhibition of tau phosphorylation. The authors investigated the role and mechanism of IGF-I gene transfer after spinal cord injury (SCI). METHODS: Studies were performed in 40 male Sprague-Dawley rats after spinal cord hemisection. The authors conducted hydrodynamics-based gene transfection in which an IGF-I plasmid was rapidly injected into the rat's tail vein 30 minutes after SCI. The animals were randomly divided into four groups: Group I, sham operated; Group II, SCI treated with pCMV-IGF-I gene; Group III, SCI treated with vehicle pCMV-LacZ gene; and Group IV, SCI only. The results showed that IGF-I gene transfer promoted motor recovery, antiinflammatory responses, and antiapoptotic effects after SCI. Using techniques of Western blotting and immunohistochemistry, the authors assessed the mechanism of IGF-I gene transfer after SCI in terms of activation of Akt, inhibition of GSK-3beta, attenuation of p35, and inhibition of tau phosphorylation. Moreover, they found that IGF-I gene transfer could block caspase-9 cleavage, increase Bcl-2 formation, and thus inhibit apoptosis after SCI. CONCLUSIONS: The intravenous administration of IGF-I after SCI activated Akt, attenuated GSK-3beta, inhibited p35 activation, diminished tau hyperphosphorylation, ended microglia and astrocyte activation, inhibited neuron loss, and significantly improved neurological dysfunction. Furthermore, IGF-I attenuated caspase-9 cleavage, increased Bcl2, and thus inhibited apoptosis after SCI.
Assuntos
Técnicas de Transferência de Genes/instrumentação , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/terapia , Animais , Astrócitos/efeitos dos fármacos , Western Blotting , Caspase 9/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Dendritos/patologia , Modelos Animais de Doenças , Genes bcl-2/genética , Genes p53/genética , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Fator de Crescimento Insulin-Like I/farmacologia , Óperon Lac/genética , Masculino , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fosforilação/efeitos dos fármacos , Plasmídeos/genética , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/patologia , Sinapses/efeitos dos fármacos , Sinapses/patologia , Proteínas tau/genéticaRESUMO
The current report summarized animal models of heatstroke experimentation that advance our current knowledge of therapeutic effects on cerebrovascular dysfunction, hypercoagulable state and/or systemic inflammation with various agents in the setting of heatstroke. This was a narrative review of selected published primary basic literature from MEDLINE for 1973-2006. It was found that rodents shared with humans almost the same heatstroke reactions such as hyperpyrexia, hypotension, hyperventilation, pulmonary edema, hepatic and renal failure, hypercoagulable state, metabolic acidosis, systemic inflammation, and cerebral ischemia, injury and dysfunction. Therefore, the rodent model would allow testing of new therapeutic strategies for heatstroke. It was found that brain cooling produced by infusion of cold (4 degrees C) normal saline via the jugular vein or whole body cooling improved survival during heatstroke by reducing cerebrovascular dysfunction, multiple organ failure, systemic inflammation and hypercoagulable state. However, even under the absence of brain or whole body cooling, these heatstroke reactions still could be reversed by treating with the following agents: (1) free radical scavengers; (2) human recombinant protein C: (3) platonin; (4) hyperbaric oxygen; (5) hydroxyethyl starch, hypertonic solution, or human albumin; (6) glucocorticoids; (7) interleukin-1 receptor antagonists; (8) L-arginine; (9) estrogen; and (10) human umbilical cord blood cells or CD +34 cells. Before initiation of heat stress, prior manipulations with one of the following measures were found to be able to protect against heatstroke syndromes: (1) systemic delivery of inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin-1A receptor antagonists, dopaminergic or serotoninergic nerve depletor or receptor antagonists, or glutamate receptor antagonists; or (2) heat shock protein 72 preconditioning.
Assuntos
Golpe de Calor/complicações , Golpe de Calor/terapia , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/prevenção & controle , Isquemia Encefálica/terapia , Golpe de Calor/patologia , Humanos , Modelos Animais , Choque/etiologia , Choque/prevenção & controle , Choque/terapiaRESUMO
BACKGROUND: Head injury is the leading cause of death and disability for patients who experienced a major accident. It has been suggested that a well-planned neurointensive care management can effectively reduce the secondary brain insults. The BTF and the AANS proposed the Guidelines for the Management of Severe Head Injury in 1995. The purpose of this study was to obtain a consensus on whether the guidelines are suitable for treating patients with severe head injury in Taiwan. METHODS: Data from patients with severe head injury were collected from 6 different medical centers in Taiwan. The methods for controlling ICP, CPP, and hyperventilation, and the medical treatment with vasopressors and sedatives have been analyzed. RESULTS: Ninety-four patients with severe head injury (GCS Assuntos
Lesões Encefálicas/terapia
, Fidelidade a Diretrizes
, Guias de Prática Clínica como Assunto
, Adulto
, Lesões Encefálicas/fisiopatologia
, Cuidados Críticos
, Feminino
, Hospitalização
, Humanos
, Pressão Intracraniana/fisiologia
, Masculino
, Estudos Retrospectivos
, Taiwan
, Resultado do Tratamento