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1.
Chinese Journal of Biotechnology ; (12): 2633-2644, 2021.
Article in Chinese | WPRIM | ID: wpr-887829

ABSTRACT

Endothelial cells that form the inner layers of both blood and lymphatic vessels are important components of the vascular system and are involved in the pathogenesis of vascular and lymphatic diseases. Angiopoietin (Ang)-Tie axis in endothelial cells is the second endothelium-specific ligand-receptor signaling system necessary for embryonic cardiovascular and lymphatic development in addition to the vascular endothelial growth factor receptor pathway. The Ang-Tie axis also maintains vascular homeostasis by regulating postnatal angiogenesis, vessel remodeling, vascular permeability, and inflammation. Therefore, the dysfunction of this system leads to many vascular and lymphatic diseases. In light of the recent advances on the role of the Ang-Tie axis in vascular and lymphatic system-related diseases, this review summarizes the functions of the Ang-Tie axis in inflammation-induced vascular permeability, vascular remodeling, ocular angiogenesis, shear stress response, atherosclerosis, tumor angiogenesis, and metastasis. Moreover, this review summarizes the relevant therapeutic antibodies, recombinant proteins, and small molecular drugs associated with the Ang-Tie axis.


Subject(s)
Humans , Angiopoietins , Endothelial Cells/metabolism , Lymphatic Diseases , Lymphatic System/metabolism , Receptor, TIE-2/metabolism , Signal Transduction , Vascular Endothelial Growth Factor A
2.
Rev. Assoc. Med. Bras. (1992, Impr.) ; 66(4): 502-506, 2020. tab, graf
Article in English | SES-SP, LILACS | ID: biblio-1136216

ABSTRACT

SUMMARY OBJECTIVE To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.


RESUMO OBJETIVO Investigar a presença das mutações no gene Angiopoietina (ANGPT1) e gene Plasminogênio (PLG) em pacientes com Angioedema Hereditário (AEH) com inibidor C1 esterase (C1-INH) normal e negativos para mutação do gene F12. MÉTODOS Foram avaliados pacientes com diagnóstico clínico de AEH sem deficiência ou disfunção de C1-INH e negativos para mutação do gene F12. Realizou-se extração, quantificação e diluição do DNA a uma concentração de 100 ng/uL, em seguida amplificação do DNA (PCR) para avaliação molecular do exon 2 do gene ANGPT1 e do exon 9 do gene PLG para identificação das mutações c.807G>T.p.A119S e c.988A>G p.K330E, respectivamente. O produto da PCR foi avaliado em eletroforese em gel de agarose 1%. Foi realizado o sequenciamento pelo método de Sanger. As análises dos eletroferogramas foram realizadas pelo programa FASTA®. RESULTADOS Foram sequenciadas amostras de 15 mulheres, idade entre 10 e 60 anos, com níveis séricos de inibidor de C1 esterase e C4 normais variando de 22 a 39mg/dL e 10 a 40mg/dL, respectivamente. Não foram identificadas mutações nos éxons analisados dos genes ANGPT1 e PLG. Entretanto no gene PLG foram encontrados polimorfismo de nucleotídeo único (SNP), em duas pacientes homozigotas e cinco heterozigotas. CONCLUSÃO Mais estudos sobre SNP são necessários para esclarecer estes achados pois eles podem ser utilizados como marcadores moleculares do AEH e alvo para novos tratamentos.


Subject(s)
Humans , Female , Child , Adolescent , Adult , Young Adult , Plasminogen/genetics , Angiopoietins/genetics , Angioedemas, Hereditary/genetics , Polymerase Chain Reaction , Complement C1 Inhibitor Protein , Middle Aged , Mutation
3.
Diabetes & Metabolism Journal ; : 364-376, 2018.
Article in English | WPRIM | ID: wpr-717365

ABSTRACT

Vision loss in diabetic retinopathy (DR) is ascribed primarily to retinal vascular abnormalities—including hyperpermeability, hypoperfusion, and neoangiogenesis—that eventually lead to anatomical and functional alterations in retinal neurons and glial cells. Recent advances in retinal imaging systems using optical coherence tomography technologies and pharmacological treatments using anti-vascular endothelial growth factor drugs and corticosteroids have revolutionized the clinical management of DR. However, the cellular and molecular mechanisms underlying the pathophysiology of DR are not fully determined, largely because hyperglycemic animal models only reproduce limited aspects of subclinical and early DR. Conversely, non-diabetic mouse models that represent the hallmark vascular disorders in DR, such as pericyte deficiency and retinal ischemia, have provided clues toward an understanding of the sequential events that are responsible for vision-impairing conditions. In this review, we summarize the clinical manifestations and treatment modalities of DR, discuss current and emerging concepts with regard to the pathophysiology of DR, and introduce perspectives on the development of new drugs, emphasizing the breakdown of the blood-retina barrier and retinal neovascularization.


Subject(s)
Animals , Mice , Adrenal Cortex Hormones , Angiopoietins , Diabetic Retinopathy , Endothelial Cells , Endothelial Growth Factors , Ischemia , Macular Edema , Models, Animal , Neuroglia , Pericytes , Retinal Neovascularization , Retinal Neurons , Retinaldehyde , Tomography, Optical Coherence , Vascular Endothelial Growth Factors
4.
Annals of Coloproctology ; : 9-15, 2017.
Article in English | WPRIM | ID: wpr-19875

ABSTRACT

PURPOSE: Angiopoietin-1 (Ang-1) plays a crucial role in vascular and hematopoietic development, mainly through its cognate receptor, Tie-2. Increased levels of Ang-2 have been shown to be correlated with abnormal tumor angiogenesis in several malignancies. Hence, we estimated the increased expression of Ang-2 relative to Ang-1 in patients with colorectal cancer and correlated our finding with prognosis in order to investigate the relationships between the expressions of Ang-1/Ang-2/Tie-2 receptor and the clinical parameters or overall survival of such patients. METHODS: We retrospectively analyzed 114 tissue samples from patients with colorectal cancer by using immunohistochemistry (IHC) to examine Ang-1, Ang-2, and Tie-2 expressions and to investigate the relationship between those expressions and clinical parameters or overall survival of such patients. A Western blot analysis was used for Ang-2 expression. RESULTS: IHC staining showed a link between Ang-1 and Tie-2 (P = 0.018), as well as meaningful correlations between Ang-2 and Tie-2 receptor (P = 0.022) and between lymph-node metastasis and Ang-2 (P = 0.025). The stronger the IHC staining for Ang-2 expression was, the shorter the cumulative survival was (P = 0.016). CONCLUSION: A relationship was found to exist between Ang-2 and Tie-2 expressions. The Ang-2 was correlated with lymph-node metastasis, and high expression of Ang-2 was indicative of poor overall survival. These findings suggest that Ang-2 is a useful prognostic marker in the management of patients with colorectal cancer. In addition, we suggest that Ang/Tie-2 signaling plays an important role in the progression of colorectal cancer.


Subject(s)
Humans , Angiopoietin-1 , Angiopoietin-2 , Angiopoietins , Blotting, Western , Colorectal Neoplasms , Immunohistochemistry , Neoplasm Metastasis , Prognosis , Receptor, TIE-2 , Retrospective Studies
5.
Journal of Zhejiang University. Medical sciences ; (6): 214-218, 2016.
Article in Chinese | WPRIM | ID: wpr-239599

ABSTRACT

Minimal change disease (MCD) is a common pathological type of nephrotic syndrome. Its main histology is the fusion of podocyte foot process. The pathogenesis of MCD is not clear, but previously it was thought to be related to immune mechanism. In recent years more studies show that podocyte injury is the key link in the pathogenesis of MCD. In MCD mouse model and human kidney tissues, the expressions of podocyte slit membrane protein-nephrin and podocin, skeleton protein-synaptopodin are decreased, and the expression of synaptopodin is correlated with the response to hormone therapy. In addition, newest studies focused on another two potocyte associated proteins, CD80 and Angiopoietin-like-4. CD80, a T cell stimulating molecule, is expressed in potocyte. Kappa B gene sequences can be activated by external microbes, antigens through acting potocytes, which can induce the upregulation of CD80 expression, cytoskeletal protein damage and the glomerular filtration rate changes, resulting in proteinuria. Angiopoietin-like-4 can be expressed in normal potocytes, but over-expression of angiopoietin-like-4 may injure the GBM charge barrier and induce the foot process fusion, leading to MCD. However, further studies on the factors inducing CD80 and Angiopoietin-like-4 expression, and the interaction between glomerular basement membrane and the two proteins are needed. Based on the mechanism of MCD, NF-kappa B inhibitors and sialylation therapy would be a novel non-immune therapy for MCD.


Subject(s)
Animals , Humans , Mice , Angiopoietin-Like Protein 4 , Angiopoietins , Metabolism , B7-1 Antigen , Metabolism , Disease Models, Animal , Intracellular Signaling Peptides and Proteins , Metabolism , Kidney , Pathology , Membrane Proteins , Metabolism , Microfilament Proteins , Metabolism , NF-kappa B , Metabolism , Nephrosis, Lipoid , Pathology , Podocytes , Pathology
6.
Acta Academiae Medicinae Sinicae ; (6): 150-154, 2016.
Article in Chinese | WPRIM | ID: wpr-289889

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the changes and value of plasma angiopoietin-related growth factor (AGF) in patients with abdominal aortic aneurysm (AAA).</p><p><b>METHODS</b>Serum AGF level was analyzed in 50 AAA patients and in 56 healthy subjects. AGF and adiponectin were quantified by enzyme-linked immunosorbent assay. Routine testing of blood biochemistry and high-sensitivity C-reactive protein were performed.</p><p><b>RESULTS</b>The plasma AGF level was significantly higher in AAA patients than in the controls [(87.91±96.87) μg/L vs. (56.89±41.32) μg/L, P=0.040],while serum adiponectin level showed no significant difference between these two groups. The plasma AGF level in patients with an AAA>5 cm and those with AAA between 3 cm and 5 cm were (96.08±68.61) μg/L and (75.27±46.05) μg/L.</p><p><b>CONCLUSIONS</b>Plasma AGF is highly expressed in AAA patients. Higher serum AGF level is associates with larger AAA. Thus, AGF may be a potential serum biomarker for AAA.</p>


Subject(s)
Humans , Adiponectin , Blood , Angiopoietin-like Proteins , Angiopoietins , Blood , Aortic Aneurysm, Abdominal , Blood , Biomarkers , Blood , C-Reactive Protein , Case-Control Studies , Enzyme-Linked Immunosorbent Assay
7.
Chinese Medical Journal ; (24): 2308-2312, 2016.
Article in English | WPRIM | ID: wpr-307418

ABSTRACT

<p><b>BACKGROUND</b>A recent study reported a positive association between elevated serum levels of angiopoietin-like protein 2 (ANGPTL2) and the development of type 2 diabetes in a general population. However, the relationship of serum ANGPTL2 levels with the risk of developing gestational diabetes mellitus (GDM) has not been reported to date. The aim of this study was to investigate the change of maternal serum ANGPTL2 concentrations in the first trimester of pregnancy and to determine whether ANGPTL2 is a biomarker for subsequent GDM development.</p><p><b>METHODS</b>We conducted a prospective, nested case-control study in a pregnancy cohort. First-trimester ANGPTL2 levels were measured using a high-resolution assay in 89 women who subsequently developed GDM and in a random sample of 177 women who remained euglycemic throughout the pregnancy. Median ANGPTL2 levels were compared using Mann-Whitney U-test. Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among ANGPTL2 quartiles.</p><p><b>RESULTS</b>The serum levels of ANGPTL2 was higher in women with GDM than that in women without GDM (3.06 [2.59, 3.65] ng/ml vs. 2.46 [2.05, 2.96] ng/ml, P = 0.003). Fasting blood glucose was higher in women with GDM than that in women without GDM (5.0 ± 0.9 mmol/L vs. 4.4 ± 0.6 mmol/L, P < 0.001). Glucose challenge test showed that the blood glucose was higher in women with GDM than that in women without GDM (9.1 ± 3.5 mmol/L vs. 6.2 ± 1.2 mmol/L, P < 0.001). A multivariate model adjusted for baseline characteristics, medical complications, and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90-fold more likely to develop GDM later in pregnancy.</p><p><b>CONCLUSIONS</b>At 11-13 weeks in pregnancies that develop GDM, the serum concentration of ANGPTL2 is increased, and it can be combined with maternal factors to provide effective early screening for GDM.</p>


Subject(s)
Female , Humans , Pregnancy , Angiopoietin-like Proteins , Angiopoietins , Blood , Biomarkers , Blood , Blood Glucose , Metabolism , Case-Control Studies , Diabetes, Gestational , Blood , Diagnosis , Odds Ratio , Prospective Studies , Risk Factors
8.
Journal of Central South University(Medical Sciences) ; (12): 851-857, 2015.
Article in Chinese | WPRIM | ID: wpr-815259

ABSTRACT

OBJECTIVE@#To investigate the association between angiopoietin-like 4 (ANGPTL4) and aldolase A (ALDOA) in human melanoma cell. 
@*METHODS@#Overexpression or knockdown of ANGPTL4 was performed in WM-115 or WM-266-4 cells, respectively. The expression of ANGPTL4 and ALDOA was measured by RT-PCR and Western blot, respectively. The promoter activity of ALDOA gene was determined by luciferase assay.
@*RESULTS@#The promoter activity of ALDOA gene and the expression of ALDOA (mRNA and protein) were increased or decreased in the melanoma cells with overexpression or knockdown of ANGPTL4, which was blocked by selective protein kinase C (PKC) inhibitor or restored by PKC agonist, respectively.
@*CONCLUSION@#ANGPTL4 promotes ALDOA expression in human melanoma cell in a PKC dependent manner.


Subject(s)
Humans , Angiopoietin-Like Protein 4 , Angiopoietins , Genetics , Metabolism , Blotting, Western , Cell Line, Tumor , Fructose-Bisphosphate Aldolase , Metabolism , Gene Knockdown Techniques , Melanoma , Genetics , Metabolism , RNA, Messenger , Genetics , Metabolism
9.
Chinese Journal of Biotechnology ; (12): 1567-1578, 2015.
Article in Chinese | WPRIM | ID: wpr-240554

ABSTRACT

Angiopoietin-like proteins are a family of proteins that are closely related to lipid, glucose and energy metabolism, as well as angiogenesis. To date, eight Angptls have been discovered, namely Angptl1 to Angptl8 that play key roles in metabolic regulation and marker assisted selection. In this review, we summarized current progress on the structure, signaling pathways, upstream regulatory genes and metabolic network of Angptl1-8. Finally, in combination with our work, the status and problems of animal breeding as well as the future prospects for Angptls were discussed.


Subject(s)
Animals , Angiopoietins , Genetics , Metabolism , Breeding , Energy Metabolism , Gene Regulatory Networks , Glucose , Metabolism , Lipid Metabolism , Metabolic Networks and Pathways , Signal Transduction
10.
Journal of Huazhong University of Science and Technology (Medical Sciences) ; (6): 615-622, 2015.
Article in English | WPRIM | ID: wpr-250369

ABSTRACT

The tyrosine kinase system angiopoietin (Ang)/Tie interacts with vascular endothelial growth factor pathway and regulates vessel quiescence in adults as well as later steps of the angiogenic cascade related to vessel maturation. Since all Angs are able to bind to Tie-2 but none binds to Tie-1, the function of Tie-2 and its ligands have captured attention. However, emerging evidence indicates unique roles of the orphan receptor Tie-1 in angiogenesis under physiological and pathological conditions. It is required for maintaining vascular endothelial cell integrity and survival during murine embryo development and in adult and may be involved in modulating differentiation of hematopoietic cells in adult. Tie-1 exhibits poor tyrosine kinase activity and signals via forming heterodimers with Tie-2, inhibiting Tie-2 signaling mediated by Angs. This inhibition can be relieved by Tie-1 ectodomain cleavage mediated by tumor- and inflammatory-related factors, which causes destabilization of vessels and initiates vessel remodeling. Up-regulated Tie-1 expression has been found not only in some leukemia cells and tumor related endothelial cells but also in cytoplasm of carcinoma cells of a variety of human solid tumors, which is associated with tumor progression. In addition, it has pro-inflammatory functions in endothelial cells and is involved in some inflammatory diseases associated with angiogenesis. Recent research indicated that Tie-1 gene ablation exhibited significant effects on tumor blood- and lymph-angiogenesis and improved anti-Ang therapy, suggesting Tie-1 may be a potential target for tumor anti-angiogenesis treatment.


Subject(s)
Animals , Humans , Mice , Angiogenesis Inhibitors , Therapeutic Uses , Angiopoietins , Genetics , Metabolism , Embryo, Mammalian , Embryonic Development , Genetics , Endothelial Cells , Metabolism , Pathology , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Neoplasms , Drug Therapy , Genetics , Metabolism , Pathology , Neovascularization, Pathologic , Drug Therapy , Genetics , Metabolism , Pathology , Protein Binding , Receptor, TIE-1 , Genetics , Metabolism , Receptor, TIE-2 , Genetics , Metabolism , Signal Transduction
11.
Arq. bras. endocrinol. metab ; 58(4): 317-327, 06/2014. tab, graf
Article in Portuguese | LILACS | ID: lil-711630

ABSTRACT

A microbiota intestinal, adquirida no período pós-natal, é composta por grande diversidade de bactérias que desempenham diferentes funções no hospedeiro humano, entre elas a absorção de nutrientes, proteção contra patógenos e modulação do sistema imune. O conteúdo bacteriano intestinal ainda não é totalmente conhecido, mas sabe-se que é influenciado por fatores internos e principalmente externos que modulam sua composição e função. Estudos indicam que a microbiota intestinal difere em indivíduos magros e obesos e ainda naqueles que mantêm hábitos alimentares diferentes. Há evidências de que as relações entre dieta, inflamação, resistência à insulina e risco cardiometabólico são em parte mediadas pela composição de bactérias intestinais. Conhecimentos sobre a microbiota poderão reverter em diferentes estratégias para manipular as populações bacterianas e promover saúde. Esta revisão aborda a relevância do conhecimento sobre o papel de fatores ou padrões alimentares na composição da microbiota, assim como mecanismos fisiopatológicos de doenças metabólicas crônicas e as potencialidades de prebióticos e probióticos sobre o perfil de risco cardiometabólico.


The gut microbiota obtained after birth is composed of a large range of bacteria that play different roles in the human host, such as nutrient uptake, protection against pathogens and immune modulation. The intestinal bacterial content is not completely known, but it is influenced by internal, and mainly by external factors, which modulate its composition and function. Studies indicate that the gut microbiota differs in lean and obese individuals, and in individuals with different food habits. There is evidence that the relationship between diet, inflammation, insulin resistance, and cardiometabolic risk are, in part, mediated by the composition of intestinal bacteria. Knowledge about the gut microbiota may result in different strategies to manipulate bacterial populations and promote health. This review discusses the relevance of understanding the role of dietary factors or patterns in the composition of the microbiota, as well as pathophysiological mechanisms of chronic metabolic diseases, and the potential of prebiotics and probiotics on the cardiometabolic risk profile.


Subject(s)
Animals , Humans , Feeding Behavior/physiology , Intestines/microbiology , Microbiota/physiology , Angiopoietins/metabolism , Diet, High-Fat/adverse effects , Glucose Metabolism Disorders/etiology , Hypertension/etiology , Lipid Metabolism Disorders/etiology , Lipopolysaccharides/metabolism , Obesity/etiology , Prebiotics , Probiotics , Risk Factors
12.
China Journal of Chinese Materia Medica ; (24): 1083-1087, 2014.
Article in Chinese | WPRIM | ID: wpr-321362

ABSTRACT

<p><b>OBJECTIVE</b>To study the effect of Astragali Radix on the denervated tibial muscle atrophy in rats, and discuss its mechanism.</p><p><b>METHOD</b>Totally 60 SPF-grade Sprague-Dawley rats were selected in the common peroneal nerve crush model, and then randomly divided into 6 groups: Astragali Radix high-dose, medium-dose, low-dose groups, the Mecobalamin group, the model group, and the sham operation group. They were administered with drugs after the operation. At 18 d, the pathological section staining and morphological analysis were performed. The wet-weight ratio and section area of tibial muscles were also measured. The real-time fluorescence quantification was adopted to detect the differential expression between Angptl4 and PI3K genes.</p><p><b>RESULT</b>(1) Wet-weight ratio: The wet-weight ratio in Astragali Radix high-dose, medium-dose groups was much higher than that in the model group (P < 0.05 or P < 0.01). (2) Section area: The sham operation group was higher, with regular morphology; Whereas the model group showed significant decrease, with chaotic structure and obvious connective tissue proliferation; Astragali Radix groups and the mecobalamin group showed relatively small section areas, with chaotic structure and unobvious connective tissue proliferation. Compared with the model group, Astragali Radix groups showed significant increase (P < 0.01). (3) Motor end plate: The sham operation group was in uniform brownish black color and oval or round shape; Astragali Radix medium-dose and high-dose group and the mecobalamin group showed rough line edges; Astragali Radix medium-dose and low-dose groups and the model group showed decline in the number, with irregular morphology, rough line edges and a light color. (4) Angptl4 and PI3K: Compared with the model group, the Astragali Radix high-dose group showed significant increase (P < 0.05).</p><p><b>CONCLUSION</b>Astragali Radix has a significant effect in preventing and treating denervated tibial muscle atrophy. It may delay the muscle atrophy by increasing Angptl4 and PI3K gene expressions.</p>


Subject(s)
Animals , Male , Rats , Angiopoietin-Like Protein 4 , Angiopoietins , Genetics , Astragalus Plant , Astragalus propinquus , Chemistry , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Pharmacology , Therapeutic Uses , Gene Expression Regulation , Muscular Atrophy , Drug Therapy , Genetics , Pathology , Phosphatidylinositol 3-Kinases , Genetics , Rats, Sprague-Dawley , Tibia
13.
Campinas; s.n; mar. 2013. 155 p. ilus, tab, graf.
Thesis in Portuguese | LILACS | ID: lil-691936

ABSTRACT

A neutropenia febril (NF) em pacientes com neoplasias hematológicas é caracterizada pelo alto risco de sepse e choque séptico. Embora a utilização de escores clínicos como o MASCC permita a identificação de pacientes de baixo risco, este escore é menos informativo em pacientes de alto risco, onde se encaixam a maioria dos pacientes com neoplasias hematológicas, além daqueles submetidos a esquemas intensivos de quimioterapia. Ao mesmo tempo, a aplicação de biomarcadores de gravidade como a procalcitonina, validados em pacientes não-neutropênicos, é controversa em pacientes com NF. A quebra da barreira endotelial é um elemento chave no choque séptico, de modo que proteínas envolvidas neste processo são candidatos atrativos como biomarcadores de gravidade na sepse. Neste estudo, avaliamos prospectivamente o valor da dosagem de VEGF-A, sFlt-1, Ang-1 e Ang-2 como biomarcadores da evolução para choque séptico em 120 pacientes com NF. Pacientes internados nas enfermarias de Hematologia e Transplante de Medula Óssea do HC da UNICAMP para tratamento de NF entre março de 2011 e 2012 foram convidados a participar. As amostras foram coletadas na manhã seguinte à entrada no estudo, junto com a coleta de exames de rotina. O estudo foi desenhado com o objetivo de mimetizar as condições de coleta e processamento das amostras, que seriam encontradas na prática clínica real. Foi avaliada a evolução para choque séptico e mortalidade em 28 dias. Os resultados foram comparados com marcadores de prognóstico clássicos como proteína C reativa, e escores MASCC e SOFA. No total, 99 pacientes preencheram os critérios de inclusão, dos quais 19,8% evoluíram com choque séptico. Não foram observadas diferenças clínicas e demográficas entre os pacientes com NF não-complicada e choque séptico, exceto pelo escore SOFA, significativamente mais elevado no segundo grupo.


Febrile neutropenia (FN) in patients with hematologic malignancies is characterized by a high risk of sepsis complications and septic shock. Although the use of clinical scores such as the MASCC allows the identification of low-risk patients, this score is much less informative in high-risk patients, a category in which most patients with hematologic malignancies, and those undergoing intensive chemotherapy regimens, fit in. At the same time, the use of classical biomarkers such as procalcitonin in non-neutropenic patients is controversial in patients with FN. Endothelial barrier breakdown is a key element in septic shock, so that proteins involved in this process are attractive candidates as biomarkers of sepsis severity. In this study, we prospectively evaluated the value of VEGF-A, sFlt-1, Ang-1 and Ang-2 serum levels as biomarkers of progression to septic shock in 120 patients with FN. Patients hospitalized in the Hematology and Bone Marrow Transplantation in-patient units of a university hospital (HC-UNICAMP) for the treatment of FN between March 2011 and March 2012 were invited to participate. Samples were collected in the following morning after study entry, along with the collection of routine labs. The study was designed to mimic the conditions of blood sample collection and processing that would be encountered in "real-world" clinical practice. Clinical outcomes were (1) progression to septic shock and (2) death within 28 days from fever onset. Results were compared with classical prognostic markers such as C-reactive protein, and MASCC and SOFA scores. In total, 99 patients met the inclusion criteria, of which 19.8% progressed to septic shock. No differences clinical and demographic differences were observed between patients with uncomplicated-FN or septic shock, except for a higher SOFA scores in the latter group.


Subject(s)
Humans , Male , Female , Hematologic Neoplasms , Neutropenia , Risk , Sepsis/complications , Angiogenesis Modulating Agents , Angiopoietins , Neoplasms , Shock, Septic
14.
Diabetes & Metabolism Journal ; : 217-224, 2013.
Article in English | WPRIM | ID: wpr-35838

ABSTRACT

Vision loss in diabetic retinopathy (DR) is attributable to retinal vascular disorders that result in macular edema and neoangiogenesis. In addition to laser photocoagulation therapy, intraocular injections of antivascular endothelial growth factor drugs have contributed to the treatment of these disease conditions. Nonetheless, the clinical feasibility of intraocular drug administration has raised an increasing demand to develop alternative drugs that can fundamentally ameliorate the retinal vascular dysfunctions in DR. For this purpose, experimental animal models that reproduce human DR would be of clinical benefit. Despite the unavailability of DR models in rats or mice, pharmacological and genetic manipulations without hyperglycemia have successfully recapitulated retinal edema and neoangiogenesis in postnatal mouse retinas, thereby enabling the understanding of the pathophysiology underlying DR. This article highlights the utility of experimental mouse models of retinal vascular abnormalities and discusses cellular and molecular mechanisms responsible for the onset and progression of DR. These approaches will lead to the identification of novel drug targets for the restoration of vascular integrity and regeneration of functional capillaries in DR.


Subject(s)
Animals , Humans , Mice , Rats , Angiopoietins , Capillaries , Diabetic Retinopathy , Endothelial Growth Factors , Hyperglycemia , Injections, Intraocular , Light Coagulation , Macular Edema , Models, Animal , Papilledema , Regeneration , Retina , Retinaldehyde , Vision, Ocular
15.
Protein & Cell ; (12): 220-230, 2013.
Article in English | WPRIM | ID: wpr-757819

ABSTRACT

Recent advances in hematopoietic stem cells (HSCs) expansion by growth factors including angiopoietin-like proteins (Angptls) have opened up the possibility to use HSCs in regenerative medicine. However, the unavailability of true in vitro HSCs expansion by these growth factors has limited the understanding of the cellular and molecular mechanism of HSCs expansion. Here, we report the functional role of mouse Angptls 1, 2, 3, 4, 6 and 7 and growth factors SCF, TPO, IGF-2 and FGF-1 on purified mouse bone-marrow (BM) Lineage(-)Sca-1(+)(Lin-Sca-1(+)) HSCs. The recombinant retroviral transduced-CHO-S cells that secrete Angptls in serum-free medium were used alone or in combination with growth factors (SCF, TPO, IGF-2 and FGF-1). None of the Angptls stimulated HSC proliferation, enhanced or inhibited HSCs colony formation, but they did support the survival of HSCs. By contrast, any of the six Angptls together with saturating levels of growth factors dramatically stimulated a 3- to 4.5-fold net expansion of HSCs compared to stimulation with a combination of those growth factors alone. These findings lead to an understanding of the basic function of Angptls on signaling pathways for the survival as well as expansion of HSCs in the bone marrow niche.


Subject(s)
Animals , Cricetinae , Mice , Angiopoietin-Like Protein 4 , Angiopoietin-like Proteins , Angiopoietins , Genetics , Metabolism , Antigens, Ly , Metabolism , Bone Marrow Cells , Cell Biology , CHO Cells , Cell Differentiation , Cell Lineage , Cell Proliferation , Cell Survival , Cells, Cultured , Cricetulus , Culture Media, Conditioned , Pharmacology , Hematopoietic Stem Cells , Cell Biology , Metabolism , Intercellular Signaling Peptides and Proteins , Pharmacology , Membrane Proteins , Metabolism , Transfection
16.
Chinese Journal of Contemporary Pediatrics ; (12): 800-805, 2013.
Article in Chinese | WPRIM | ID: wpr-345703

ABSTRACT

With the advances in pre- and post-natal medical care, the incidence of bronchopulmonary dysplasia (BPD) is on the rise, while its pathogenesis remains not clear. New BPD theory shows that the core pathogenesis of BPD is simple alveolar structure and pulmonary microvascular abnormalities that eventually lead to reduced pulmonary gas exchange, so the research on pulmonary microvascular development was gradually taken seriously. Pulmonary angiogenesis and vascular development require the participation of various cytokines and signaling pathways, the most important of which include VEGF/VEGFR pathway, Ang/Tie pathway, Ephrins/Eph pathway, and Notch/Jagged1 pathway. These cytokines and signaling pathways play important roles in pulmonary vascular development.


Subject(s)
Humans , Infant, Newborn , Angiopoietins , Physiology , Blood Vessels , Embryology , Bronchopulmonary Dysplasia , Cytokines , Physiology , Ephrins , Physiology , Lung , Neovascularization, Physiologic , Receptors, Notch , Physiology , Signal Transduction , Physiology , Vascular Endothelial Growth Factor A , Physiology
17.
Journal of Experimental Hematology ; (6): 73-77, 2013.
Article in Chinese | WPRIM | ID: wpr-325209

ABSTRACT

This study was aimed to investigate the effect of valproic acid (VPA), a histone deacetylase inhibitor, on angiogenesis of acute myeloid leukemia in vivo and vitro, and to explore its molecular mechanism. Human t (8;21) AML cell line Kasumi-1 cells were treated with VPA at different concentration for 3 d, the mRNA and protein expression levels of Ang1 and Ang2 were determined by semi-quantitative RT-PCR and Western blot respectively. Nude mice model with xenograft Kasumi-1 tumor was established by subcutaneous inoculation of Kasumi-1 cells. The CD34, Ang1 and Ang2 protein levels were analyzed by immunohistochemistry method. The mRNA and protein expression levels of Ang1, Ang2 and VEGF were determined by semi-quantitative RT-PCR and Western blot. The results showed that in vitro, VPA at 3 mmol/L downregulated the Ang mRNA relative expression level for Ang1 from 0.360 ± 0.116 to 0.040 ± 0.008, Ang2 from 0.540 ± 0.049 to 0.146 ± 0.038. The animal experiment further verified that VPA 500 mg/kg, ip, for 14 d, reduced the relative expression of Ang1, Ang2 and VEGF mRNA and proteins in Kasumi-1 tumor of nude mice, and reduced microvascular density in xenograft tumor of nude mice (8.470 ± 0.300 vs 2.600 ± 0.200). It is concluded that VPA significantly inhibits tumor angiogenesis through the regulation of angiopoietins, thereby inhibits the proliferation and metastasis of leukemia cells.


Subject(s)
Animals , Female , Humans , Mice , Angiopoietins , Metabolism , Antigens, CD34 , Metabolism , Cell Line, Tumor , Leukemia, Myeloid, Acute , Metabolism , Pathology , Mice, Inbred BALB C , Mice, Nude , Neovascularization, Pathologic , Metabolism , RNA, Messenger , Genetics , Valproic Acid , Pharmacology , Vascular Endothelial Growth Factor A , Metabolism , Xenograft Model Antitumor Assays
18.
Journal of Experimental Hematology ; (6): 7-11, 2012.
Article in Chinese | WPRIM | ID: wpr-331032

ABSTRACT

This study was purposed to explore the expression of Ang-1, Ang-2, Tie-2, Kindlin-2, Kindlin-3 in different leukemia cell lines and bone marrow of acute myeloid leukemia (AML) patients and its clinical significance. The levels of Ang-1, Ang-2, Tie-2, Kindlin-2, Kindlin-3 in bone marrow of AML patients and nontumorous control group as well as leukemia cell lines (K562, KG-1a, U937, HL-60 and Jurkat) were detected by RQ-PCR. The difference of positive rate and expression level between AML patients and controls was analyzed. The relation between 5 genes and their relationship with typing and prognosis of AML were investigated. The results showed that Ang-1, Ang-2, Kindlin-3 expressed in K562, KG-1a, U937, HL-60 and Jurkat cells. Tie-2 only expressed in KG-1a and HL-60 cells. Kindlin-2 expressed in K562, KG-1a and HL-60 cells. All of these 5 genes expressed in AML patients and nontumorous controls. The expression level of Ang-1 and Ang-2 in patients with higher WBC count (≥ 30 × 10(9)/L) was significantly higher than that in patients with lower WBC (< 30 × 10(9)/L, P < 0.001, P < 0.001). The expression level of Ang-1 and Ang-2 in patients with t(8;21) or t(15;17) was significantly lower (P < 0.001, P = 0.005). In the NCCN better-risk group, Ang-1 expressed lower (P = 0.020). The group with lower expression of Ang-1 showed a higher complete remission (CR) rate (P = 0.027). The expression level of Kindlin-2 was lower in AML patients (P = 0.010), lower in patients with higher WBC (≥ 30 × 10(9)/L, P = 0.020), and higher in patients with t(8;21) or t(15;17). The expression levels of both Kindlin-2 and Kindlin-3 were significantly higher after CR (P < 0.001, P = 0.004). It is concluded that Ang-1 closely correlated with the poor prognosis of AML. Kindlin-2 lowly expresses in AML, which has a close relation with the favorable prognosis of AML. Kindlin-2 can be a marker for favorable prognosis of AML.


Subject(s)
Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Angiopoietins , Metabolism , Case-Control Studies , Cell Line, Tumor , Leukemia, Myeloid, Acute , Diagnosis , Metabolism , Membrane Proteins , Metabolism , Neoplasm Proteins , Metabolism , Prognosis
19.
Journal of Southern Medical University ; (12): 1614-1618, 2011.
Article in Chinese | WPRIM | ID: wpr-333849

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effect of ANGPTL4 gene silencing on the migration of human colon cancer cells in vitro.</p><p><b>METHODS</b>The expression of ANGPTL4 in human colorectal cancer cell lines was detected by semi-quantitative RT-PCR. Following stable transfection with a short-hairpin RNA (shRNA) targeting ANGPTL4 gene in HT29 cells, ANGPTL4 mRNA and protein expressions were detected by semi-quantitative RT-PCR and direct ELISA, respectively, and the changes in cell migration ability and cell morphology were observed with transwell and immunofluorescence assays.</p><p><b>RESULTS</b>ANGPTL4 was expressed in most of the colorectal cancer cell lines. Compared with the control groups, HT29 cells with shRNA-mediated ANGPTL4 gene silencing showed significantly decreased expression of ANGPTL4 mRNA and protein (P<0.05) and lowered cell migration ability possibly due to decreased pseudopodia formation.</p><p><b>CONCLUSION</b>ANGPTL4 was expressed in most colorectal cancer cell lines. Decreased ANGPTL4 gene expression can inhibit the cell migration and pseudopodia formation in HT29 cells.</p>


Subject(s)
Humans , Angiopoietin-Like Protein 4 , Angiopoietins , Genetics , Cell Movement , Colorectal Neoplasms , Genetics , Pathology , Gene Silencing , HT29 Cells , RNA, Small Interfering , Genetics
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