RESUMO
BACKGROUND AND PURPOSE: High blood pressure (BP) at presentation is associated with poor outcomes in acute ischaemic stroke, but serial BP measurements may better delineate the clinical implications of BP. The aim was to investigate the association between various BP parameters and functional outcomes in acute ischaemic stroke patients treated with endovascular thrombectomy (EVT). METHODS: This study reports a retrospective analysis of a prospective registry of a comprehensive stroke centre. Patients treated with EVT due to large vessel occlusion in the anterior circulation were enrolled. BP was measured hourly during the first 24 h after admission. Associations of various BP parameters, including BP variability, with functional outcomes at 3 months, including good outcomes (modified Rankin Scale score of 0-2), were analysed. RESULTS: Of the 378 enrolled patients (mean age 70 ± 11 years, male 54.2%), 313 (82.8%) achieved successful reperfusion after EVT, and 149 (39.4%) had good outcomes at 3 months. Higher mean systolic BP [each 10 mmHg increase, odds ratio 0.82 (0.69-0.97)] and higher systolic successive variation (SV) [each 10% increase, odds ratio 0.37 (0.18-0.76)] were associated with a reduced likelihood of achieving good outcomes. In addition, reperfusion status after EVT moderated the influence of higher systolic SV on good outcomes (Pint = 0.05). CONCLUSION: The results showed that a higher mean systolic BP and systolic SV during the first 24 h of EVT reduced the likelihood of good outcomes at 3 months. The effects of these parameters on outcomes are more substantial amongst patients with successful reperfusion after EVT, suggesting that different BP control strategies should be employed according to reperfusion status.
Assuntos
Pressão Sanguínea/fisiologia , Isquemia Encefálica/cirurgia , Procedimentos Endovasculares/métodos , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: In this study, we aimed to identify demographic and clinical variables that correlate with perceived information provision among cancer patients and determine the association of information provision with decisional conflict (DC). PATIENTS AND METHODS: We enrolled a total of 625 patients with cancer from two Korean hospitals in 2012. We used the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire (QLQ-INFO26) to assess patients' perception of the information received from their doctors and the Decisional Conflict Scale (DCS) to assess DC. To identify predictive sociodemographic and clinical variables for adequate information provision, backward selective logistic regression analyses were conducted. In addition, adjusted multivariate logistic regression analyses were carried out to identify clinically meaningful differences of perceived level of information subscales associated with high DC. RESULTS: More than half of patients with cancer showed insufficient satisfaction with medical information about disease (56%), treatment (73%), other services (83%), and global score (80%). In multiple logistic regression analyses, lower income and education, female, unmarried status, type of cancer with good prognosis, and early stage of treatment process were associated with patients' perception of inadequate information provision. In addition, Information about the medical tests with high DCS values clarity [adjusted odds ratio (aOR), 0.54; 95% confidence interval (CI) 0.30-0.97] and support (aOR, 0.53; 95% CI 0.33-0.85) showed negative significance. For inadequate information perception about treatments and other services, all 5 DCS scales (uncertainty, informed, values clarity, support, and effective decision) were negatively related. Global score of inadequate information provision also showed negative association with high DCS effective decision (aOR, 0.43; 95% CI 0.26-0.71) and DCS uncertainty (aOR, 0.46; 95% CI 0.27-0.77). CONCLUSION: This study found that inadequate levels of perceived information correlated with several demographic and clinical characteristics. In addition, sufficient perceived information levels may be related to low levels of DC.
Assuntos
Comunicação , Conflito Psicológico , Tomada de Decisões , Relações Médico-Paciente , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Educação de Pacientes como Assunto , Qualidade de Vida , Fatores Socioeconômicos , Inquéritos e QuestionáriosRESUMO
Compromised T-cell immunity persists for up to 1 year after autologous stem cell transplantation (ASCT), and patients treated with ASCT are more likely to develop atypical lymphoid hyperplasia that mimics tumor recurrence. Here, we present a case of cervical lymphadenitis due to cytomegalovirus (CMV) reactivation in a patient who had undergone ASCT for Burkitt lymphoma, which mimicked tumor recurrence on computed tomography and positron emission tomography-computed tomography 6 months after ASCT. This lesion was confined to the regional lymph nodes and was not accompanied by signs of systemic involvement, such as fever, splenomegaly, an elevated C-reactive protein level, or viremia. The localized CMV lymphadenitis resolved spontaneously without treatment after 6 months (12 months after ASCT) and the elevated CMV immunoglobulin-M titer normalized 6 months after resolution. Our experience with this case suggests that cautious follow-up without anti-CMV treatment should be considered in cases of post-ASCT localized CMV lymphadenitis without systemic involvement in patients with complete engraftment.
Assuntos
Infecções por Citomegalovirus/patologia , Linfadenite/virologia , Transplante de Células-Tronco/efeitos adversos , Adulto , Linfoma de Burkitt , Humanos , Linfadenite/patologia , Masculino , Recidiva Local de NeoplasiaRESUMO
Schwannomas are benign tumors arising from the peripheral nerves with a Schwann cell sheath. Schwannomas can be found in almost every region, but are usually associated with cranial, spinal, sympathetic and peripheral nerves. Schwannoma in lower extremity is relatively common and most are associated with sciatic nerve, peroneal nerve and tibial nerve. However, schwannoma arising in the tendon or paratenon is extremely rare. We report a rare case of a 25-year-old male patient with a schwannoma originating from the paratenon of semitendinosus muscle without evidences of any neurologic symptoms. The clinical history, plain radiographs, magnetic resonance imaging, and pathologic findings of the reported patient have been reviewed. The tumor was fully excised by dissecting a tendon sheath of semitendinosus muscle.
Assuntos
Neoplasias Musculares/cirurgia , Músculo Esquelético/cirurgia , Neurilemoma/cirurgia , Tendões/cirurgia , Adulto , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Musculares/diagnóstico , Neurilemoma/diagnóstico , Tendões/patologiaRESUMO
AIM: Serum antithyroglobulin antibody (TgAb) has been reported as a surrogate marker for differentiated thyroid cancer (DTC) in some conditions. We investigated changes in serum TgAb levels after stimulation with thyroid-stimulating hormone (TSH) and the clinical implications for monitoring DTC. PATIENTS, METHODS: We retrospectively enrolled 53 DTC patients who had undergone total thyroidectomy and were negative for serum Tg and positive for TgAb. Patients underwent high-dose radioactive iodine treatment, and serum TgAb was measured before (TgAbBAS) and after TSH stimulation (TgAbSTIM). TgAb was followed up 6 to 12 months later (TgAbF/U). The change in TgAb after TSH stimulation (∆TgAbSTIM) was calculated as a percentage of the baseline level. Patient disease status was classified into no residual disease (ND) and residual or recurred disease (RD) by follow-up imaging studies and pathologic data. The characteristics and diagnostic value of serum TgAb levels and ∆ TgAbSTIM were investigated with respect to disease status. RESULTS: 38 patients were in the ND group and 15 were in the RD group. TgAbBAS, TgAbSTIM and TgAbF/U were significantly higher in the RD compared to the ND group (p = 0.0008, 0.0002, and < 0.0001, respectively). ∆TgAbSTIM was also significantly higher in the RD group (p = 0.0009). In the patients who presented with obviously high (≥ 50%) or low (< -50%) ∆ TgAbSTIM, the proportions in the RD group were markedly different at 100% and 7%, respectively. ∆ TgAbSTIM had significant diagnostic value for RD (p < 0.001). CONCLUSION: The change in serum TgAb level after TSH stimulation is different between the RD and ND groups, and thus, it may be used as a surrogate diagnostic marker for DTC when the serum Tg is negative and TgAb is positive.
Assuntos
Autoanticorpos/sangue , Biomarcadores Tumorais/sangue , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Tireoglobulina/sangue , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/diagnóstico , Tireotropina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Neoplasias da Glândula Tireoide/cirurgia , Resultado do TratamentoRESUMO
Resistance to chemotherapeutic drugs is a significant clinical problem in the treatment of cancer and this resistance has been linked to the cellular expression of multidrug-efflux transporters. The aim of this study was to explore the role of HOXC6 in the regulation of multidrug resistance (MDR) to chemotherapeutic drugs. The HOXC6 gene was identified as being overexpressed in drug-resistant cells compared with parental cell lines. Transfection assays demonstrated that HOXC6 activated MDR-1 promoter activity. A series of MDR-1 promoter deletion mutants was examined and the minimal HOXC6-responsive region was identified to be in the TAAT motif (-2243 bp) of the MDR-1 promoter. Interestingly, overexpression of HOXC6 in the parental cell lines resulted in the upregulation of MDR-1 expression. The inhibition of HOXC6 using small interfering RNA led to the repression of MDR-1. We determined that knockdown of HOXC6 expression in MDR cells increased their sensitivity to paclitaxel. Flow cytometry analysis suggested that siHOXC6 could induce paclitaxel-induced apoptosis and that this was accompanied by an increased accumulation and a decreased release of paclitaxel. Taken together, our findings suggest that HOXC6 expression is an important mechanism of chemotherapeutic drug resistance via its regulation of MDR-1.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Transcrição Gênica , Antineoplásicos/farmacologia , Apoptose/genética , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Rodamina 123/metabolismo , Transcrição Gênica/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND: In healthy elderly people, silent brain infarctions (SBIs) have been recognized as common lesions. In this study, we evaluated the association between SBI located outside the perforating artery territory (PAT) and paradoxical embolism detected by agitated saline transcranial Doppler (TCD) monitoring in healthy subjects. METHODS: This was a prospective observational study undertaken by a university health promotion center for healthy subjects and by a university stroke center for acute stroke patients. We defined SBI as evidence on fluid-attenuation inversion recovery (FLAIR) magnetic resonance imaging (MRI) of one or more infarcts, without history of corresponding stroke or transient ischaemic attack. We also evaluated in all subjects the neuroimaging indicator of microangiopathy leukoaraiosis (LA). This study is registered with ClinicalTrials.gov, number NCT01429948. RESULTS: Amongst 1103 consecutive healthy adults who underwent MRI, 347 (31%) had one or more SBIs located outside the PAT, suggesting embolism. Amongst them, 253 subjects underwent agitated saline TCD monitoring and 128 (51%) had right-to-left shunts (RLS). The prevalence of RLS was similar to cryptogenic embolic stroke (62.0%, P = 0.056), but higher than in patients with other stroke subtypes (36.2%, P = 0.021). Amongst subjects with SBI, absence of LA was the only factor associated with RLS (OR 1.78; 95% CI 1.01-3.14; P = 0.046). CONCLUSION: Our results suggest that paradoxical embolism may play an important role in the development of SBI outside the PAT in apparently healthy adults.
Assuntos
Infarto Encefálico/etiologia , Embolia Paradoxal/patologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/epidemiologia , Infarto Encefálico/patologia , Embolia Paradoxal/diagnóstico por imagem , Feminino , Forame Oval Patente/diagnóstico por imagem , Forame Oval Patente/patologia , Humanos , Leucoaraiose/complicações , Leucoaraiose/diagnóstico por imagem , Leucoaraiose/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média/patologia , Neuroimagem/métodos , Prevalência , Estudos Prospectivos , República da Coreia/epidemiologia , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/patologia , Ultrassonografia Doppler TranscranianaRESUMO
Endocrine therapies that inhibit estrogen receptor (ER)-α signaling are the most common and effective treatment for ER-α-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The aim of this study was to elucidate the mechanisms by which downregulation of CDK10 expression confers resistance to tamoxifen in breast cancer. Here, we show that peptidyl-prolyl isomerase Pin1 downregulates CDK10 protein as a result of its interaction with and ubiquitination of CDK10, thereby affecting CDK10-dependent Raf-1 phosphorylation (S338). Pin1(-/-) mouse embryonic fibroblasts (MEFs) show higher CDK10 expression than Pin1(+/+) MEFs, whereas CDK10 protein was downregulated in the rescued Pin1(-/-) MEFs after reexpression of Pin1. Pin1 silencing in SKBR-3 and MCF7 cells increased the CDK10 expression. In human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 cells, immunohistochemical staining and immunoblotting analysis shows an inverse correlation between the expression of CDK10 and the degree of tamoxifen resistance. There was also a positive correlation between the high level of P-Raf-1 (Ser338) and Pin1 in human tamoxifen-resistant breast cancer and tamoxifen-resistant MCF7 (TAMR-MCF7) cells. Importantly, 4-OH tamoxifen (4-OHT), when used in combination with overexpressed CDK10 or Raf-1 inhibitor, increased cleaved PARP and DNA fragmentation to inhibit cologenic growth of MCF7 cells and Tamoxifen-resistant MCF7 cells, respectively. On the basis of these findings, we suggest that the Pin1-mediated CDK10 ubiquitination is a major regulator of tamoxifen-resistant breast cancer cell growth and survival.
Assuntos
Quinases Ciclina-Dependentes/metabolismo , Peptidilprolil Isomerase/metabolismo , Tamoxifeno/farmacologia , Ubiquitina/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quinases Ciclina-Dependentes/genética , Resistencia a Medicamentos Antineoplásicos/genética , Embrião de Mamíferos/citologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células HEK293 , Humanos , Immunoblotting , Camundongos , Camundongos Knockout , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/genética , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteólise , Proteínas Proto-Oncogênicas c-raf/metabolismo , Interferência de RNARESUMO
Pitting corrosion is a damage mechanism quite serious and dangerous in both carbon steel boiler tubes for power plants which are vital to most industries and stainless steels for orthopedic human implants whose demand, due to the increase of life expectation and rate of traffic accidents, has sharply increased. Reliable methods to characterize this kind of damage are becoming increasingly necessary, when trying to evaluate the advance of damage and to establish the best procedures for component inspection in order to determine remaining lives and failure mitigation. A study about the uncertainties on the topographies of corrosion pits from 3D SEM images, obtained at low magnifications (where errors are greater) and different stage tilt angles were carried out using an in-house software previously developed. Additionally, measurements of pit depths on biomaterial surfaces, subjected to two different surface treatments on stainless steels, were carried out. The different depth distributions observed were in agreement with electrochemical measurements.
RESUMO
Panax ginseng is widely used as herbal medicine in East Asia and the pharmacological effects of P. ginseng against certain chronic diseases might be explained by its antioxidative effects. Here, we show that ginsenoside Rd significantly increases both cellular glutathione (GSH) contents and the protein level of gamma-glutamylcysteine ligase (gamma-GCL) heavy chain in H4IIE cells (a rat hepatocyte cell line). Subcellular fractionation and Western blot analysis revealed that ginsenoside Rd increased the nuclear level of p65, but not of Nrf2. Moreover, ginsenoside Rd increased luciferase reporter gene activity in cells transfected with nuclear factor-kappaB (NF-kappaB) binding site-containing -1088 bp gamma-GCL promoter. However, ginsenoside Rd-inducible reporter activity was abolished when cells were transfected with NF-kappaB deletion mutant. These effectsof ginsenoside Rd are suggested to underlie the putative anti-oxidative effect of Panax ginseng.
Assuntos
Antioxidantes/farmacologia , Ginsenosídeos/farmacologia , Glutamato-Cisteína Ligase/biossíntese , Glutationa/metabolismo , NF-kappa B/fisiologia , Animais , Western Blotting , Linhagem Celular , Indução Enzimática , Genes Reporter/efeitos dos fármacos , Glutamato-Cisteína Ligase/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Ratos , Fator de Transcrição RelA/biossíntese , Fator de Transcrição RelA/genéticaRESUMO
Chemopreventive agents induce a battery of genes whose protein products can protect cells from chemical-induced carcinogenesis. In this study, we isolated four different glycosides (1 acteoside; 2 purpureaside A; 3 calceolarioside B; and 4, plantainoside D) from the leaves of Digitalis purpurea and studied their abilities to induce glutathione S-transferase (GST) and their protective efficiencies against aflatoxin B1-induced cytotoxicity in H4IIE cells. Of these four glycosides, acteoside significantly inhibited the cytotoxicity induced by aflatoxin B1 (AFB1) and also selectively increased GSTalpha protein levels. Reporter gene analysis using an antioxidant response element (ARE) containing construct and subcellular fractionation assays, revealed that GSTalpha induction by acteoside might be associated with Nrf2/ARE activation. The results suggest that acteoside possesses a potent hepatoprotective effect against AFB1 and that it can be applied as a potential chemopreventive agent.
Assuntos
Anticarcinógenos , Glicosídeos Digitálicos/farmacologia , Digitalis/química , Aflatoxina B1/antagonistas & inibidores , Aflatoxina B1/toxicidade , Carcinógenos/antagonistas & inibidores , Carcinógenos/toxicidade , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Indução Enzimática/efeitos dos fármacos , Glutationa Transferase/biossíntese , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imuno-Histoquímica , Luciferases , Fator 2 Relacionado a NF-E2/metabolismo , Folhas de Planta/química , Transporte Proteico/genéticaRESUMO
OBJECTIVE: The authors compared the neural circuits recruited for working memory (WM) in obsessive-compulsive disorder (OCD) patients both at a neutral state and at a symptom provoked state. METHOD: Twelve OCD patients, and 12 age-, and sex-matched healthy subjects underwent [(15)O]H(2)O positron emission tomography (PET) scanning, while performing WM task. In the patients, the tasks were performed both in the neutral and in the symptom provoked states. RESULTS: In the OCD patients, the right caudate and the right superior parietal cortex (rSPC) displayed activations for WM at the neutral state, while the right cingulate cortex and rSPC displayed activations for WM at the symptom provoked state. Path analysis revealed that the activity of the caudate and orbitofrontal cortex was altered according to the interaction between WM and symptom provocation. CONCLUSION: The interaction between symptom provocation and WM occurring in the fronto-striatal system may hold the key to the neurobiology of OCD.
Assuntos
Encéfalo/fisiopatologia , Memória de Curto Prazo , Vias Neurais/fisiopatologia , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/psicologia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Testes Psicológicos , Valores de Referência , Análise e Desempenho de TarefasRESUMO
This technical note reports the use of symphyseal distraction with stepwise osteotomy in a case of lower anterior crowding and rotation in the incisor area. This technique allows for easy dental decompensation and reduced presurgical orthodontic time in skeletal class III cases.
Assuntos
Má Oclusão Classe III de Angle/cirurgia , Mandíbula/cirurgia , Osteogênese por Distração/métodos , Osteotomia/métodos , Adulto , Humanos , Maxila/cirurgia , Osteotomia de Le Fort , Técnicas de Movimentação DentáriaRESUMO
Amentoflavone is a bi-flavonoid compound with anti-fungal and anti-inflammatory activities. We isolated amentoflavone from Selaginella tamariscina (Selaginellaceae) and studied its effects on nuclear factor-kappaB (NF-kappaB)-mediated inducible nitric oxide synthase (iNOS) gene expression in RAW 264.7 cells. Amentoflavone inhibited the production of nitric oxide in a concentration-dependent manner and also blocked the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS). To clarify the mechanistic basis for its inhibition of iNOS induction, we examined the effect of amentoflavone on the transactivation of iNOS gene by luciferase reporter activity using -1.59 kb flanking region. Amentoflavone potently suppressed the reporter gene activity. The LPS-induced activation of NF-kappaB was also found to be significantly blocked by amentoflavone, but AP-1 activation was unaffected. Furthermore, the nuclear translocation of p65 by LPS was inhibited by amentoflavone. NF-kappaB activation is controlled by the phosphorylation and subsequent degradation of I-kappaBalpha, and the cytosolic degradation of I-kappaBalpha was found to be inhibited by amentoflavone. These findings suggest that the inhibition of LPS-induced NO formation by amentoflavone is due to its inhibition of NF-kappaB by blocking I-kappaBalpha degradation, which may be the mechanistic basis of the anti-inflammatory effects of amentoflavone.
Assuntos
Biflavonoides/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Biflavonoides/química , Biflavonoides/isolamento & purificação , Linhagem Celular , Relação Dose-Resposta a Droga , Indução Enzimática/efeitos dos fármacos , Indução Enzimática/fisiologia , Macrófagos/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico Sintase/biossíntese , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , SelaginellaceaeRESUMO
AIMS: The specific objective of this study was to determine acute and long-term effects of cyclo (his-pro) (CHP) plus zinc and l-histidine (CZH) treatment on glucose metabolism in genetically obese (ob/ob), type 2 diabetic mice. METHODS: Acute effects of 0.3 mg of CHP plus 10 mg of zinc and 0.5 mg of l-histidine/kg body weight (BW) on fed blood glucose concentrations and 3-h average of above fasting blood glucose concentrations (TAFGCs), an index of oral glucose tolerance test, in lean and ob/ob mice were determined. To evaluate long-term effects of CZH on TAFGCs, lean and ob/ob mice were treated with drinking water containing increasing doses of CHP (0, 0.5, 1.0 or 1.5 mg/l) plus 10 mg zinc and 0.5 mg of l-histidine/l for 3 weeks. During the treatment period, fed blood glucose concentrations, BW and food and water intake were determined. At the end of the treatment, fasting blood glucose concentrations, TAFGC and fed plasma insulin concentrations were determined. RESULTS: Blood glucose concentrations significantly decreased when CZH was administered acutely via gastric gavage in food-deprived ob/ob mice. Similarly, 1.0 mg/l CHP treatment of mice with fixed amounts of 10 mg zinc and 0.5 mg l-histidine/l was optimal to decrease fed blood glucose and plasma insulin concentrations during a 3-week treatment period in ob/ob mice. TAFGC values in these mice also improved most significantly with the same combination of CHP, zinc and l-histidine used to test for fed blood glucose and plasma insulin levels. Fasting blood glucose concentrations and BW gains also decreased in ob/ob mice treated with 1.0 mg of CHP/l plus the same amount of zinc and l-histidine used in the above experiments. No effects of CZH treatment in lean mice were observed. CONCLUSIONS: CZH is effective in decreasing blood glucose concentrations in genetically obese (ob/ob), type 2 diabetic mice. These data support our working hypothesis that CZH may be an important anti-hyperglycaemic agent.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Obesidade , Peptídeos Cíclicos/uso terapêutico , Piperazinas/uso terapêutico , Zinco/uso terapêutico , Animais , Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Aumento de Peso/efeitos dos fármacosRESUMO
The mechanisms of cadmium-induced toxicity may include oxidative stress, altered redox homeostasis, and injuries to organelles. The current study was designed to study the effect of decreased cellular glutathione (GSH) content by sulfur amino acid deprivation on cadmium toxicity and to identify the signaling pathways responsible for the cytotoxicity. GSH content was increased by cadmium in H4IIE cells prior to cell death, which was prevented by excess GSH or cysteine. Cell viability, however, was not improved by GSH or cysteine complexation of cadmium. Cadmium-induced cytotoxicity was 40-fold potentiated in cells with decreased GSH by sulfur amino acid deprivation. Cadmium in combination with decreased GSH markedly increased apoptotic cell death. Mitogen-activated protein kinases including extracellular signal-regulated kinase 1/2, p38 kinase and c-Jun N-terminal kinase (JNK) were all activated 1-12 hr after sulfur amino acid deprivation. U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene), which inhibited activation of extracellular signal-regulated kinase1/2 and p38 kinase in cells under sulfur amino acid deprivation, completely prevented potentiation in Cd-induced cytotoxicity and apoptosis. Potentiation of cadmium toxicity by sulfur amino acid deprivation was prevented in part by either PD98059 or SB203580, or in cells stably expressing dominant negative mutant of JNK1, and to greater extents by PD98059 in combination with either SB203580 or JNK1(-) transfection. These results demonstrated that decreased cellular GSH content potentiated cytotoxicity induced by cadmium at the level of human exposure, and that the potentiation of cytotoxicity resulted from activation of extracellular signal-regulated kinase1/2 in conjunction with p38 kinase or JNK.
Assuntos
Aminoácidos Sulfúricos/metabolismo , Butadienos/farmacologia , Cádmio/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nitrilas/farmacologia , Aminoácidos/metabolismo , Animais , Cisteína/metabolismo , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Flavonoides/farmacologia , Glutationa/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno , Ratos , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
Bdellin-KL is a trypsin-plasmin inhibitor from Hirudo nipponia, whose N-terminal sequence was identified as a non-classical Kazal-type. A cDNA clone encoding the inhibitor was isolated by reverse transcription-PCR and 5' rapid amplification of cDNA ends. The cDNA showed an open reading frame of 155 amino acids comprising one signal peptide and two separated domains. The C-terminal domain consists of distinct internal repeats, including HHEE and HHDD. The bdellin-KL sequence, from the constructed genomic library of Korean leech, was determined for the 2109 bases comprising the open reading frame and flanking regions (3' and 5'). The promoter region contains potential regulatory sequence motifs, including TATA, CAAT, and GC boxes. To characterize the properties of each domain, an N-terminal fragment was prepared by limited proteolysis of the intact protein. The inhibitory activity of the region was as potent as that of the intact protein. This suggests that the compact domain plays an important part in the inhibitory action of bdellin-KL. The C-terminal domain was revealed to have binding affinity to ions such as Ca(2+), Zn(2+), Fe(3+), and Fe(2+) without an influence on the inhibitory activity. This study demonstrates that bdellin-KL may be a novel bifunctional protein with two distinct domains.
Assuntos
Antifibrinolíticos/metabolismo , DNA Complementar/isolamento & purificação , Sanguessugas/química , Compostos Orgânicos , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores da Tripsina/metabolismo , Animais , Sequência de Bases/genética , Sítios de Ligação/fisiologia , Cálcio/química , Cálcio/metabolismo , Ferro/química , Ferro/metabolismo , Dados de Sequência Molecular , Fases de Leitura Aberta/genética , Estrutura Terciária de Proteína/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Zinco/química , Zinco/metabolismoRESUMO
Exposure to nitrosamines may be the occupational risk factor for liver cirrhosis. 2-(Allylthio)pyrazine, a chemopreventive agent, inhibits CYP2E1 and induces phase II enzymes. We examined the effects of 2-(allylthio)pyrazine on hepatic fibrosis, a prepathologic state of cirrhosis, and on the expression of transforming growth factor-beta1 induced by dimethylnitrosamine. Treatment of rats with dimethylnitrosamine for 4 weeks increased plasma alanine/aspartate amino-transferase and y-glutamyl transpeptidase activities, and bilirubin content, whereas the total plasma protein and albumin levels were decreased. 2-(Allylthio)pyrazine inhibited dimethylnitrosamine-induced increases in the enzyme activities and bilirubin, and restored the plasma protein and albumin contents. Masson's trichrome staining showed that dimethylnitrosamine induced liver fibrosis, the extent of which was reduced by 2-(allylthio)pyrazine treatments. Reverse transcription-polymerase chain reaction analysis revealed that 2-(allylthio)pyrazine inhibited production of transforming growth factor-beta1 mRNA by dimethylnitrosamine. These results demonstrated that 2-(allylthio)pyrazine might inhibit dimethylnitrosamine-induced liver fibrosis due to suppression of CYP2E1 expression and transforming growth factor-beta1 production.
Assuntos
Dimetilnitrosamina/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Cirrose Hepática/prevenção & controle , Pirazinas/uso terapêutico , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Dimetilnitrosamina/toxicidade , Fígado/efeitos dos fármacos , Fígado/enzimologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transaminases/sangue , Fator de Crescimento Transformador beta1RESUMO
A probabilistic atlas of the human brain (Statistical Probabilistic Anatomical Maps: SPAM) was developed by the international consortium for brain mapping (ICBM). It is a good frame for calculating volume of interest (VOI) in many fields of brain images. After calculating the counts in VOI using the product of probability of SPAM images and counts in FDG images, asymmetric indices (AI) were calculated and used for finding epileptogenic zones in mesial temporal lobe epilepsy (mTLE). FDG PET images from 18 surgically confirmed mTLE patients and 22 age-matched controls were spatially normalized to the average brain MRI template of ICBM. Counts from normalized PET images were multiplied with the probability of 12 VOIs from SPAM images in both temporal lobes. Finally AI were calculated on each pair of VOIs, and compared with visual assessment. If AI of mTLE patients were not within 2.9 standard deviation from those of normal control group (P < 0.008; Bonferroni correction for P < 0.05), epileptogenic zones were considered to be found successfully. The counts of VOIs in the normal control group were symmetric (AI < 4.3%, paired t test P > 0.05) except for those of the inferior temporal gyrus (P < 0.001). By AIs in six pairs of VOIs, PET in mTLE had deficit on one side (P < 0.05). Lateralization was correct in only 14/18 of patients by AI, but 17/18 were consistent with visual inspection. In three patients with normal AI, PET images were symmetric on visual inspection. The asymmetric indices obtained by taking the product of the statistical probability anatomical map and FDG PET, correlated well with visual assessment in mTLE patients. SPAM is useful for the quantification of VOIs in functional images.
Assuntos
Mapeamento Encefálico , Epilepsia do Lobo Temporal/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/estatística & dados numéricos , Modelos Estatísticos , Tomografia Computadorizada de Emissão/estatística & dados numéricos , Adulto , Dominância Cerebral/fisiologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Fluordesoxiglucose F18 , Seguimentos , Hipocampo/diagnóstico por imagem , Hipocampo/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico por imagem , Psicocirurgia , Valores de Referência , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/cirurgiaRESUMO
PURPOSE: DA-125 [(8S,10S)-8-(3-Aminopropanoyloxyacetyl)-10-[(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacene-dione hydrochloride] is a novel anthracycline derivative with anticancer activity. In the present study, we compared the cytotoxicity of DA-125 with that of doxorubicin in H4IIE rat hepatoma cells and investigated the mechanistic basis. Because activation of MAP kinases, in particular c-Jun N-terminal kinase (JNK), is implicated in apoptotic cell death, the signaling pathways responsible for DA-125-induced apoptosis were studied. METHODS: Cytotoxicity and apoptosis were measured in H4IIE cells and cells were stably transfected with a dominant-negative mutant of JNK1 (JNK1-) by MTT and TUNEL assays. Inhibition of topoisomerase II activity was determined in vitro. Drug accumulation and DNA binding affinity were determined by fluorescence spectroscopy. RESULTS: The cytotoxicity of DA-125 was greater than that of doxorubicin (IC50 11.5 vs 70 microM). DA-125 induced apoptosis with 30-fold greater potency than doxorubicin. Inhibition of topoisomerase II by DA-125 was fourfold greater. The presence of excess beta-alanine, a DA-125 moiety, failed to alter cytotoxicity and accumulation of DA-125, indicating that the improved cytotoxicity of DA-125 did not result from the beta-alanine moiety. Greater cellular accumulation of DA-125 correlated with its high-affinity DNA binding. Although neither PD98059 nor SB203580 altered the degree of cytotoxicity induced by DA-125, JNK1 cells exhibited about a twofold greater viability than control cells. DA-125-induced apoptosis was also decreased in JNK1- -transfected cells. CONCLUSIONS: DA-125 potently inhibited topoisomerase II activity and induced apoptosis by a high rate of prooxidant production. DA-125 exhibited high-affinity DNA binding with improved cellular drug accumulation. Apoptosis induced by DA-125 involved the pathway of JNK1, but not ERK1/2 or p38 kinase.