RESUMO
BACKGROUND/AIMS: To investigate the effect of cognitive impairment and X-linked inhibitor of apoptosis protein (XIAP) on glucolipid metabolism. MATERIALS AND METHODS: ß-amyloid (Aß 1-42) was injected into the hippocampus of rats to establish a cognitive impairment model. Trans-activator of transcription (TAT)-XIAP fusion protein (the TAT-XIAP group), PBS (the model group), or XIAP antisense oligonucleotides (the ASODN group) was injected into the lateral ventricles of the rats to increase and decrease the activity of XIAP in the hippocampus. To determine the level of blood glucose and lipids, adenosine monophosphate-activated protein kinase (AMPK) expression of liver and hipppocamual neuronal apoptosis. RESULTS: The levels of FPG, TG, TC and LDL were significantly higher in the TAT-XIAP group, the model group and the ASODN group than in the blank group (P < 0.05); however, the HDL level showed no significant change in all groups of rats. The apoptosis indexes of the rat hippocampal CA1 neuron were 68.44 ± 4.31%, 13.21 ± 2.30%, 56.68 ± 4.771%, and 87.51 ± 6.63% in the model group, the blank group, the TAT-XIAP group and the ASODN group, respectively. Gastrointestinal motility was less frequent (per time unit) in the model group, the ASODN group and the TAT-XIAP group than in the blank group. Compared with the model group, gastrointestinal motility was significantly less frequent in the ASODN group and was significantly more frequent in the TAT-XIAP group. Compared with the blank group, the model group had a significantly lower gastric emptying rate and intestinal propulsive rate. Compared with the model group, the gastric emptying rate and intestinal propulsive rate were significantly lower in the ASODN group and were significantly higher in the TAT-XIAP group. Compared with the blank group, the expressions of AMPK mRNA, and AMPK protein were significantly reduced in the model group, the TAT-XIAP group, and the ASODN group. AMPK expression was significantly increased in the TAT-XIAP group and was significantly decreased in the ASODN group than in the model group. CONCLUSION: Cognitive impairment and hippocampal neuron apoptosis can cause glucose and lipids metabolic abnormalities, possibly by regulating gastrointestinal motility and AMPK expression in the liver. The changes in the function of XIAP, which is an anti-apoptotic protein in the hippocampus, may affect the metabolism of glucose and lipids.
Assuntos
Transtornos Cognitivos/metabolismo , Glucose/metabolismo , Hipocampo/fisiopatologia , Metabolismo dos Lipídeos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Glicemia/metabolismo , Transtornos Cognitivos/sangue , Transtornos Cognitivos/fisiopatologia , Feminino , Motilidade Gastrointestinal , Hipocampo/metabolismo , Lipídeos/sangue , Masculino , Ratos Sprague-Dawley , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/sangueAssuntos
Doença de Crohn/genética , Testes Genéticos , Criança , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Educação Médica Continuada , Fármacos Gastrointestinais/uso terapêutico , Predisposição Genética para Doença , Humanos , Infliximab/uso terapêutico , Masculino , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/sangueRESUMO
PURPOSE: To investigate the relationship of the apoptosis regulators X-linked inhibitor of apoptosis (XIAP) and ubiquitin specific protease 8 (USP8) with clinical parameters, survival and response to chemotherapy in patients with advanced stages of non-small cell lung cancer (NSCLC). METHODS: The study included 34 NSCLC patients (28 females, 6 males) and 44 healthy individuals (17 males, 27 females) as a control group. XIAP and USP8 levels were determined by ELISA. RESULTS: The median serum XIAP level of the patients and the control group showed no significant difference. USP8 level was higher in patients than in controls (p<0.0001). In univariate analysis, there was no significant relationship between XIAP and USP8 serum levels and age, sex, performance status, weight loss, stage of disease, histopatological type and response to chemotherapy. Response to chemotherapy did not differ between the high and low XIAP and USP8 groups . There was no significant difference in progression- free survival (PFS) (p=0.432 and p=0.50, respectively) and overall survival (OS) (p=0.989 and p=0.90, respectively) between the low and high XIAP and USP8 groups. CONCLUSION: No relationship was found in serum XIAP and USP8 levels with clinical parameters, response to chemotherapy, PFS and OS in patients with advanced stages of NSCLC.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Endopeptidases/sangue , Complexos Endossomais de Distribuição Requeridos para Transporte/sangue , Neoplasias Pulmonares/sangue , Ubiquitina Tiolesterase/sangue , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoAssuntos
Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteínas Inibidoras de Apoptose/sangue , Pênfigo/sangue , Pênfigo/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/sangue , Idoso , Relação Dose-Resposta a Droga , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Índice de Gravidade de Doença , Survivina , Resultado do Tratamento , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/sangueRESUMO
X-linked lymphoproliferative disease is a rare congenital immunodeficiency that is most often caused by mutations in SH2D1A, the gene encoding signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). XLP caused by SAP deficiency is most often characterized by fulminant mononucleosis/EBV- associated hemophagocytic lymphohistiocytosis (HLH), lymphoma, and dysgammaglobulinemia. XLP has also been found to be caused by mutations in BIRC4, the gene encoding X-linked inhibitor of apoptosis (XIAP). Patients with XIAP deficiency often present with HLH or recurrent HLH, which may or may not be associated with EBV. XLP is prematurely lethal in the majority of cases. While genetic sequencing can provide a genetic diagnosis of XLP, a more rapid means of diagnosis of XLP is desirable. Rapid diagnosis is especially important in the setting of HLH, as this may hasten the initiation of life-saving medical treatments and expedite preparations for allogeneic hematopoietic cell transplantation (HCT). Flow cytometry offers a means to quickly screen patients for XLP. Flow cytometry can be used to measure lymphocyte SAP or XIAP protein expression, and can also be used to observe lymphocyte phenotypes and functional defects that are unique to XLP. This review will give a brief overview of the clinical manifestations and molecular basis of SAP deficiency and XIAP deficiency, and will focus on the use of flow cytometry for diagnosis of XLP.
Assuntos
Citometria de Fluxo/métodos , Doenças Genéticas Ligadas ao Cromossomo X , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transtornos Linfoproliferativos , Mutação , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Citometria de Fluxo/normas , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Linfócitos/metabolismo , Transtornos Linfoproliferativos/sangue , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/genética , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Fatores de Tempo , Transplante Homólogo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/sangueRESUMO
BACKGROUND: Deficiency of X-linked inhibitor of apoptosis (XIAP), caused by BIRC4 gene mutations, is the second known cause of X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency that often presents with life-threatening hemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis of the known genetic causes of HLH, including XIAP deficiency, facilitates the initiation of life-saving treatment and preparation for allogeneic hematopoietic cell transplantation (HCT). Until now, a rapid screening test for XIAP deficiency has not been available. METHODS: To develop a flow cytometric screening test for XIAP deficiency, we first used lymphoblastic cell lines generated from controls and patients with BIRC4 mutations to identify two commercially available antibodies specific for native intracellular XIAP. Next, we used these antibodies to study control whole blood leukocyte XIAP expression. We then studied XIAP expression in leukocytes from patients with XLP due to BIRC4 mutations, maternal carriers, and patients following HCT. RESULTS: XIAP was expressed by the majority of all whole blood nucleated cells in normal controls. In contrast, XIAP was absent or decreased in all lymphocyte subsets, monocytes and granulocytes from four unrelated patients with XLP due to BIRC4 mutations. Bimodal distribution of XIAP expression was evident in two maternal carriers, with significant skewing toward cells expressing normal XIAP. Bimodal distribution was also observed in a patient following HCT. CONCLUSIONS: Flow cytometric analysis of intracellular XIAP provides a rapid screening test for XLP due to XIAP deficiency. It also allows carrier detection and can be used to monitor donor versus recipient reconstitution following HCT.