Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.375
Filtrar
1.
Adv Exp Med Biol ; 1131: 1013-1030, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646543

RESUMO

Endothelial colony forming cells (ECFCs) represent the only known truly endothelial precursors. ECFCs are released in peripheral circulation to restore the vascular networks dismantled by an ischemic insult or to sustain the early phases of the angiogenic switch in solid tumors. A growing number of studies demonstrated that intracellular Ca2+ signaling plays a crucial role in driving ECFC proliferation, migration, homing and neovessel formation. For instance, vascular endothelial growth factor (VEGF) triggers intracellular Ca2+ oscillations and stimulates angiogenesis in healthy ECFCs, whereas stromal derived factor-1α promotes ECFC migration through a biphasic Ca2+ signal. The Ca2+ toolkit endowed to circulating ECFCs is extremely plastic and shows striking differences depending on the physiological background of the donor. For instance, inositol-1,4,5-trisphosphate-induced Ca2+ release from the endoplasmic reticulum is downregulated in tumor-derived ECFCs, while agonists-induced store-operated Ca2+ entry is up-regulated in renal cellular carcinoma and is unaltered in breast cancer and reduced in infantile hemangioma. This remodeling of the Ca2+ toolkit prevents VEGF-induced pro-angiogenic Ca2+ oscillations in tumor-derived ECFCs. An emerging theme of research is the dysregulation of the Ca2+ toolkit in primary myelofibrosis-derived ECFCs, as this myeloproliferative disorder may depend on a driver mutation in the calreticulin gene. In this chapter, I provide a comprehensive, but succinct, description on the architecture and role of the intracellular Ca2+ signaling toolkit in ECFCs derived from umbilical cord blood and from peripheral blood of healthy donors, cancer patients and subjects affected by primary myelofibrosis.


Assuntos
Sinalização do Cálcio , Células Endoteliais , Cálcio , Proliferação de Células , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Humanos , Neoplasias/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi ; 37(10): 732-736, 2019 Oct 20.
Artigo em Chinês | MEDLINE | ID: mdl-31726502

RESUMO

Objective: To observe the changes of extracellular histones and pulmonary microvascular endothelial cells, and study the activating role of extracellular histones to pulmonary microvascular endothelial cells in the pathogenesis of acute respiratory distress syndrome (ARDS) . Methods: The correlation of the severity of acute lung injury with extracellular histones and pulmonary endothelial damage was studied through mice model, and acute lung injury was produced by aspiration of different concentrations of hydrochloric acid (0.01、0.1、0.3 and 0.5 mol/L, 2 ml/kg). Tumor necrosis factor-α (TNF-α), soluble thrombomodulin (sTM) and lung pathological change were measured. The pro-inflammatory role of extracellular histones was tested by injecting calf thymus histones (CTH) or specific anti-H4 antibody through tail vein. The direct activating role of extracellular histones to pulmonary microvascular endothelial cells was studied through pulmonary endothelial model. Results: The extracellular histones in plasma were increased obviously 6h after aspiration of different concentrations of hydrochloric acid in mice. A positive correlation was seen between extracellular histones and concentrations of aspirated hydrochloric acid (r=0.9180, P<0.05). The sTM in plasma also showed a positive correlation with concentrations of aspirated hydrochloric acid (r=0.8701, P<0.05). Merely administering CTH could not only increase TNF-α and sTM in plasma but also cause obvious lung injury, while specific anti-H4 antibody could relieve the inflammation and lung damage caused by CTH. Extracellular histones could directly damage pulmonary endothelial cells to release sTM in pulmonary endothelial model in vitro, while anti-H4 antibody could protect the endothelial cells. Conclusion: Extracellular histones are the key endogenic inflammatory mediators during the pathogenesis of ARDS caused by aspiration of hydrochloric acid, which could promote inflammation by directly activating pulmonary endothelial cells.


Assuntos
Lesão Pulmonar Aguda/patologia , Células Endoteliais/citologia , Histonas/sangue , Síndrome do Desconforto Respiratório do Adulto/patologia , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Células Endoteliais/patologia , Ácido Clorídrico , Inflamação , Pulmão , Camundongos , Síndrome do Desconforto Respiratório do Adulto/induzido quimicamente , Trombomodulina/sangue , Fator de Necrose Tumoral alfa/sangue
3.
Toxicol Lett ; 317: 13-23, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31562912

RESUMO

Combination antiretroviral therapy (cART) has been hugely successful in reducing the mortality associated with human immunodeficiency virus (HIV) infection, resulting in a growing population of people living with HIV (PLWH). Since PLWH now have a longer life expectancy, chronic comorbidities have become the focus of the clinical management of HIV. For example, cardiovascular complications are now one of the most prevalent causes of death in PLWH. Numerous epidemiological studies show that antiretroviral treatment increases cardiovascular disease (CVD) risk and early onset of CVD in PLWH. Nucleoside reverse transcriptase inhibitors (NRTIs) are the backbone of cART, and two NRTIs are typically used in combination with one drug from another drug class, e.g., a fusion inhibitor. NRTIs are known to induce mitochondrial dysfunction, contributing to toxicity in numerous tissues, such as myopathy, lipoatrophy, neuropathy, and nephropathy. In in vitro studies, short-term NRTI treatment induces an endothelial dysfunction with an increased reactive oxygen species (ROS) production; long-term NRTI treatment decreases cell replication capacity, while increasing mtROS production and senescent cell accumulation. These findings suggest that a mitochondrial oxidative stress is involved in the pathogenesis of NRTI-induced endothelial dysfunction and premature senescence. Mitochondrial dysfunction, defined by a compromised mitochondrial quality control via biogenesis and mitophagy, has a causal role in premature endothelial senescence and can potentially initiate early cardiovascular disease (CVD) development in PLWH. In this review, we explore the hypothesis and present literature supporting that long-term NRTI treatment induces vascular dysfunction by interfering with endothelial mitochondrial homeostasis and provoking mitochondrial genomic instability, resulting in premature endothelial senescence.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Senescência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Animais , Fármacos Anti-HIV/administração & dosagem , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Esquema de Medicação , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Metabolismo Energético/efeitos dos fármacos , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
4.
Adv Exp Med Biol ; 1161: 149-167, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562629

RESUMO

Inflammation is a common underlying factor in a diversity of ocular diseases, ranging from macular degeneration, autoimmune uveitis, glaucoma, diabetic retinopathy and microbial infection. In addition to the variety of known cellular mediators of inflammation, such as cytokines, chemokines and lipid mediators, there is now considerable evidence that sphingolipid metabolites also play a central role in the regulation of inflammatory pathways. Various sphingolipid metabolites, such as ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and lactosylceramide (LacCer) can contribute to ocular inflammatory diseases through multiple pathways. For example, inflammation generates Cer from sphingomyelins (SM) in the plasma membrane, which induces death receptor ligand formation and leads to apoptosis of retinal pigment epithelial (RPE) and photoreceptor cells. Inflammatory stress by reactive oxygen species leads to LacCer accumulation and S1P secretion and induces proliferation of retinal endothelial cells and eventual formation of new vessels. In sphingolipid/lysosomal storage disorders, sphingolipid metabolites accumulate in lysosomes and can cause ocular disorders that have an inflammatory etiology. Sphingolipid metabolites activate complement factors in the immune-response mediated pathogenesis of macular degeneration. These examples highlight the integral association between sphingolipids and inflammation in ocular diseases.


Assuntos
Oftalmopatias , Inflamação , Esfingolipídeos , Apoptose , Células Endoteliais/citologia , Células Endoteliais/patologia , Oftalmopatias/fisiopatologia , Humanos , Inflamação/fisiopatologia , Esfingolipídeos/metabolismo
5.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261857

RESUMO

Cystathionine-γ-lyase (CSE) isa hydrogen sulfide (H2S)-synthesizing enzyme that promotesinflammation by upregulating H2S in sepsis. Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells (liver sieve) that undergo alteration during sepsis and H2S plays a role in this process. Substance P (SP) is encoded by the preprotachykinin A (PPTA) gene, and promotes inflammation in sepsis; however, its regulation by H2S is poorly understood. Furthermore, the interaction between H2S and SP in modulating LSEC fenestrations following sepsis remains unclear. This study aimed to investigate whether CSE/H2S regulates SP and the neurokinin-1 receptor (NK-1R) andmodulates fenestrations in LSECs following caecalligation and puncture (CLP)-induced sepsis. Here we report thatthe absence of either CSE or H2S protects against liver sieve defenestration and gaps formation in LSECsin sepsis by decreased SP-NK-1R signaling. Following sepsis, there is an increased expression of liver CSE and H2S synthesis, and plasma H2S levels, which were aligned with higher SP levels in the liver, lungs and plasma and NK-1R in the liver and lungs. The genetic deletion of CSE led to decreased sepsis-induced SP and NK-1R in the liver, lungs and plasma SP suggesting H2S synthesized through CSE regulates the SP-NK-1R pathway in sepsis. Further, mice deficient in the SP-encoding gene (PPTA) preservedsepsis-induced LSEC defenestrationand gaps formation, as seen by maintenance of patent fenestrations and fewer gaps. In conclusion, CSE/H2S regulates SP-NK-1R and modulates LSEC fenestrations in sepsis.


Assuntos
Cistationina gama-Liase/metabolismo , Fígado/metabolismo , Sepse/metabolismo , Substância P/metabolismo , Sulfitos/metabolismo , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores da Neurocinina-1/metabolismo , Substância P/genética
6.
Nat Commun ; 10(1): 3071, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296856

RESUMO

The formation of new blood vessels is essential for normal development, tissue repair and tumor growth. Here we show that inhibition of the kinase p38α enhances angiogenesis in human and mouse colon tumors. Mesenchymal cells can contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. We show that p38α negatively regulates an angiogenic program in mesenchymal stem/stromal cells (MSCs), multipotent progenitors found in perivascular locations. This program includes the acquisition of an endothelial phenotype by MSCs mediated by both TGF-ß and JNK, and negatively regulated by p38α. Abrogation of p38α in mesenchymal cells increases tumorigenesis, which correlates with enhanced angiogenesis. Using genetic models, we show that p38α regulates the acquisition of an endothelial-like phenotype by mesenchymal cells in colon tumors and damage tissue. Taken together, our results indicate that p38α in mesenchymal cells restrains a TGF-ß-induced angiogenesis program including their ability to transdifferentiate into endothelial cells.


Assuntos
Neoplasias do Colo/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Neoplasias Experimentais/patologia , Neovascularização Patológica/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Carcinógenos/administração & dosagem , Carcinógenos/toxicidade , Proliferação de Células , Transdiferenciação Celular , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Transição Epitelial-Mesenquimal , Técnicas de Silenciamento de Genes , Células HT29 , Humanos , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Quinase 14 Ativada por Mitógeno/genética , Neoplasias Experimentais/induzido quimicamente , RNA Interferente Pequeno/metabolismo
7.
Nature ; 572(7767): 62-66, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341278

RESUMO

Recent work has shown that meningeal lymphatic vessels (mLVs), mainly in the dorsal part of the skull, are involved in the clearance of cerebrospinal fluid (CSF), but the precise route of CSF drainage is still unknown. Here we reveal the importance of mLVs in the basal part of the skull for this process by visualizing their distinct anatomical location and characterizing their specialized morphological features, which facilitate the uptake and drainage of CSF. Unlike dorsal mLVs, basal mLVs have lymphatic valves and capillaries located adjacent to the subarachnoid space in mice. We also show that basal mLVs are hotspots for the clearance of CSF macromolecules and that both mLV integrity and CSF drainage are impaired with ageing. Our findings should increase the understanding of how mLVs contribute to the neuropathophysiological processes that are associated with ageing.


Assuntos
Líquido Cefalorraquidiano/metabolismo , Sistema Glinfático/anatomia & histologia , Sistema Glinfático/fisiologia , Vasos Linfáticos/anatomia & histologia , Vasos Linfáticos/fisiologia , Base do Crânio/anatomia & histologia , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Células Endoteliais/citologia , Células Endoteliais/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Sistema Glinfático/citologia , Sistema Glinfático/patologia , Proteínas de Homeodomínio/metabolismo , Vasos Linfáticos/citologia , Vasos Linfáticos/patologia , Linfedema/metabolismo , Linfedema/patologia , Imagem por Ressonância Magnética , Masculino , Camundongos , Espaço Subaracnóideo/anatomia & histologia , Fatores de Tempo , Proteínas Supressoras de Tumor/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 3 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
Cell Biochem Funct ; 37(6): 432-442, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31318458

RESUMO

Advanced glycation end products (AGEs) are naturally occurring molecules that start to accumulate from embryonic developmental stages and form as part of normal ageing. When reducing sugars interact with and modify proteins or lipids, AGE production occurs. AGE formation accelerates in chronic hyperglycemic conditions, and high AGE levels have been associated with the pathogenesis of various diseases. In addition, enhanced levels of AGEs have been linked to delayed wound healing as seen in patients with diabetes mellitus. Research has provided numerous ways in which a high AGE concentration results in impaired wound healing, including oxidative stress, structural and functional changes to proteins important in wound repair, an enhanced inflammatory response by activation of transcription factors, and possible exaggerated apoptosis of cells necessary to the wound repair process. Apoptosis is a naturally occurring cell death process that is significant for normal tissue functioning and plays an important role in wound repair by preventing a prolonged inflammatory response and excessive scar formation. Abnormal apoptosis affects wound healing, resulting in slow healing wounds. This review will summarize the role of AGEs in wound healing, focusing on the mechanisms by which AGEs lead to apoptosis in various cell types. The review provides the way forward for medical research and molecular studies as it focuses on the mechanisms by which AGEs induce apoptosis in various cell types, including fibroblasts, osteoblasts, neuronal cells, and endothelial cells. Reviewing the mechanisms of AGE-linked apoptosis is important in understanding the impact of high AGE levels in delayed wound healing in diabetic patients due to abnormal apoptosis of cells necessary to the wound healing process.


Assuntos
Apoptose , Produtos Finais de Glicação Avançada/metabolismo , Cicatrização , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neurônios/metabolismo , Neurônios/patologia , Osteoblastos/metabolismo , Osteoblastos/patologia
9.
Medicine (Baltimore) ; 98(27): e16277, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277155

RESUMO

Kaposi sarcoma (KS) is an endothelial tumor etiologically related to Kaposi sarcoma herpesvirus (KSHV) infection. The aim of our study was to screen out candidate genes of KSHV infected endothelial cells and to elucidate the underlying molecular mechanisms by bioinformatics methods. Microarray datasets GSE16354 and GSE22522 were downloaded from Gene Expression Omnibus (GEO) database. the differentially expressed genes (DEGs) between endothelial cells and KSHV infected endothelial cells were identified. And then, functional enrichment analyses of gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed. After that, Search Tool for the Retrieval of Interacting Genes (STRING) was used to investigate the potential protein-protein interaction (PPI) network between DEGs, Cytoscape software was used to visualize the interaction network of DEGs and to screen out the hub genes. A total of 113 DEGs and 11 hub genes were identified from the 2 datasets. GO enrichment analysis revealed that most of the DEGs were enrichen in regulation of cell proliferation, extracellular region part and sequence-specific DNA binding; KEGG pathway enrichments analysis displayed that DEGs were mostly enrichen in cell cycle, Jak-STAT signaling pathway, pathways in cancer, and Insulin signaling pathway. In conclusion, the present study identified a host of DEGs and hub genes in KSHV infected endothelial cells which may serve as potential key biomarkers and therapeutic targets, helping us to have a better understanding of the molecular mechanism of KS.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Herpesvirus Humano 8 , Mapas de Interação de Proteínas/genética , Sarcoma de Kaposi/genética , Biomarcadores Tumorais/biossíntese , DNA de Neoplasias/genética , Células Endoteliais/patologia , Células Endoteliais/virologia , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Humanos , Mapeamento de Interação de Proteínas/métodos , Sarcoma de Kaposi/metabolismo , Sarcoma de Kaposi/virologia
10.
Nat Commun ; 10(1): 2761, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235698

RESUMO

Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias do Sistema Nervoso Central/patologia , Células Endoteliais/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/patologia , Diferenciação Celular/genética , Linhagem Celular , Neoplasias do Sistema Nervoso Central/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Técnicas de Inativação de Genes , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mutação com Perda de Função , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/metabolismo
11.
Acta Cir Bras ; 34(5): e201900501, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166464

RESUMO

PURPOSE: To analyze the effects of ischemic preconditioning (IPC) in the expression of apoptosis-related genes in rat small intestine subjected to ischemia and reperfusion. METHODS: Thirty anesthetized rats underwent laparotomy and were drive into five groups: control (CG); ischemia (IG); ischemia and reperfusion (IRG); IPC and ischemia (IG+IPC); IPC and ischemia and reperfusion (I/RG+IPC). Intestinal ischemia was performed by clamping the superior mesenteric artery for 60 minutes, whereas reperfusion lasted for 120 minutes. IPC was carried out by one cycle of 5 minutes of ischemia followed by 10 minutes of reperfusion prior to the prolonged 60-minutes-ischemia and 120-minutes-reperfusion. Thereafter, the rats were euthanized and samples of small intestine were processed for histology and gene expression. RESULTS: Histology of myenteric plexus showed a higher presence of neurons presenting pyknotic nuclei and condensed chromatin in the IG and IRG. IG+IPC and I/RG+IPC groups exhibited neurons with preserved volume and nuclei, along with significant up-regulation of the anti-apoptotic protein Bcl2l1 and down-regulation of pro-apoptotic genes. Moreover, Bax/Bcl2 ratio was lower in the groups subjected to IPC, indicating a protective effect of IPC against apoptosis. CONCLUSION: Ischemic preconditioning protect rat small intestine against ischemia/reperfusion injury, reducing morphologic lesions and apoptosis.


Assuntos
Proteínas Reguladoras de Apoptose/análise , Apoptose/genética , Precondicionamento Isquêmico/métodos , Jejuno/irrigação sanguínea , Jejuno/patologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Proteínas Reguladoras de Apoptose/genética , Constrição , Regulação para Baixo , Células Endoteliais/patologia , Expressão Gênica , Masculino , Artéria Mesentérica Superior , Isquemia Mesentérica/genética , Isquemia Mesentérica/patologia , Distribuição Aleatória , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Reprodutibilidade dos Testes
12.
Virchows Arch ; 475(3): 357-364, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31218404

RESUMO

Chronic intervillositis of unknown etiology (CIUE) is a rare placental lesion associated with infiltration of mononuclear inflammatory cells into the intervillous space, poor perinatal outcomes (intrauterine fetal demise or fetal growth restriction), and high rates of recurrence. CD39 is the ectonucleotidase that protects tissues from inflammatory stress and cell injury, which is localized on the surface of villi in normal placentas; however, its expression and role in CIUE are unknown. The aims of this retrospective study were to determine the expression of CD39 in CIUE and its significance in pregnancy outcomes. We compared the number of CD68- and CD3-positive cells, CD39 expression, and complement 4d (C4d) and fibrin deposition in placental tissues from patients with CIUE (n = 22) and gestational age-matched controls (n = 20), and between CIUE pregnancies with poor and good outcomes. The numbers of CD68- or CD3-positive cells were significantly higher (P < 0.0001), whereas CD39 expression on the surface of villi and endothelial cells of the stem villi was significantly lower in the CIUE group than that in controls (45% vs. 95%, P < 0.0001 and 77% vs. 96%, P < 0.001, respectively). C4d and fibrin deposition were also significantly increased in CIUE compared with those of controls. Furthermore, CD39 downregulation and the number of CD68 cells were strongly associated with poor pregnancy outcomes (P < 0.01 and P < 0.05, respectively), but other histological parameters (CD3, C4d, and fibrin) did not show this association. Our study suggests that CD39 downregulation is a useful marker of CIUE and is associated with poor pregnancy outcomes in patients with CIUE.


Assuntos
Apirase/metabolismo , Doenças Placentárias/patologia , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Apirase/fisiologia , Complexo CD3/análise , Vilosidades Coriônicas/patologia , Regulação para Baixo , Células Endoteliais/patologia , Feminino , Retardo do Crescimento Fetal/patologia , Humanos , Placenta/patologia , Doenças Placentárias/metabolismo , Gravidez , Resultado da Gravidez/epidemiologia , Recidiva , Estudos Retrospectivos
13.
Cancer Sci ; 110(8): 2658-2666, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31199029

RESUMO

Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34-positive and vascular endothelial growth factor A (VEGF-A)-positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin-positive and α smooth muscle actin (αSMA)-positive cancer-associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net-anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF-targeted intraperitoneal anti-cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin-anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.


Assuntos
Fibrina/metabolismo , Invasividade Neoplásica/patologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/patologia , Adulto , Idoso , Ascite/metabolismo , Ascite/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/patologia , Peritônio/metabolismo , Peritônio/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Int J Oncol ; 55(1): 211-222, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180531

RESUMO

Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent­induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co­culture system was then used to analyze the mechanisms of tumor cell­mediated disruption of lymphatic vessels. Time­lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.


Assuntos
Antígenos Nucleares/metabolismo , Autoantígenos/metabolismo , Células Endoteliais/patologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Adesão Celular/fisiologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/metabolismo , Esferoides Celulares
15.
Life Sci ; 232: 116590, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31228514

RESUMO

Endothelial cell (EC) apoptosis is fundamental for the pathophysiology of atherosclerosis, in which microRNAs (miRNAs) emerge as critical regulators. miR-122 has been shown to regulate the apoptosis of various cell types, however, whether miR-122 is associated with atherosclerosis and EC apoptosis remains unknown. In this study, we found that miR-122 expression was increased in the aortic ECs of ApoE-/- mice fed with a high-fat diet (HFD), as compared to normal-diet (ND), implying a potential association between miR-122 elevation and atherogenesis. In addition, in vitro, miR-122 expression was also induced in human aortic ECs (HAECs) by the treatment of oxidized low-density lipoprotein (ox-LDL), a common atherogenic factor. Functionally, miR-122 knockdown suppressed ox-LDL-induced apoptosis of HAECs, suggesting a pro-apoptotic role of miR-122 in HAECs under this pro-atherogenic condition. Further evidence revealed that the X-linked inhibitor-of-apoptosis protein (XIAP) was directly targeted and suppressed by miR-122 in HAECs, and more importantly, XIAP knockdown diminished miR-122 effect on apoptosis, thus establishing XIAP as a prominent target that mediates miR-122 regulation of the apoptosis of HAECs. Together, these results may identify miR-122 as a novel regulator in EC apoptosis, which offers it as a possible target for therapeutic interventions of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , MicroRNAs/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Aorta/metabolismo , Apolipoproteínas E/metabolismo , Apoptose/fisiologia , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , Transdução de Sinais , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
16.
Anticancer Res ; 39(6): 2739-2747, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177109

RESUMO

BACKGROUND/AIM: The aim of the present study was to investigate the vascular normalization effect of traditional Chinese medicine Astragalus membranaceus (AM) and Curcuma wenyujin (CW) on tumor-derived endothelial cells (TECs). MATERIALS AND METHODS: TECs were isolated from the xenografted HCC cell line HepG2 expressing red fluorescent protein (RFP). The effect of AM and CW on TECs proliferation was measured using the CCK8 assay. The vascular normalization potential of AM and CW was assessed using a tube formation assay. Immunocytochemistry was performed to assess the effect of AM and CW on the expression of angiogenic maker CD34 and hypoxia-inducible factor HIF1a. RESULTS: The isolated TECs and endothelioma (EOMA) cells did not differ with regard to the expression levels of endothelial markers CD34, VEGFR-1, VEGFR-2, PDGFR-α and PDGFR-ß. All AM, CW, AM+CW and Nintedanib (Nin) showed a dose-dependent increasing inhibition effect on either TECs or EOMA cells. AM, CW and AM+CW significantly reduced HIF1a expression, increased CD34 expression and enhanced endothelial network formation in TECs or EOMA cells compared to the control. CONCLUSION: AM and CW promoted vascular normalization in tumor-derived endothelial cells of HCC, through increased expression of CD34 and reduced expression of HIF1a.


Assuntos
Antígenos CD34/metabolismo , Carcinoma Hepatocelular/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/citologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Astragalus propinquus/química , Carcinoma Hepatocelular/irrigação sanguínea , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcuma/química , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Medicina Tradicional Chinesa , Camundongos , Transplante de Neoplasias , Transdução de Sinais/efeitos dos fármacos
17.
J Toxicol Sci ; 44(5): 317-326, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068537

RESUMO

The purpose of this study was to explore whether renal endothelial cell injury is associated with oxidative stress in trichloroethylene (TCE)-induced immune kidney damage by detecting adhesion molecules and oxidative stress indexes. In this study, a mouse model of skin sensitization with the antioxidant Tempol was used to explore the mechanism. Blood urea nitrogen (BUN), creatinine (Cre), and histological examination were used for kidney function evaluation. Kidney homogenates were used for detecting renal nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD) and malondialdehyde (MDA). Renal endothelial nitric oxide synthase (eNOS), E-selectin, vascular cell adhesion molecule (VCAM-1) and intercellular adhesion molecule (ICAM-1) protein levels were measured by immunohistochemical and Western blot. We found that BUN and Cre levels increased in the TCE sensitization positive group and the TCE+Tempol sensitization positive group. In the TCE sensitization positive group, a partial area of vacuolar degeneration and lysed epithelial cells were observed in renal tubules. In TCE+Tempol sensitization positive group, small areas were also found to be vacuolar degenerated and renal tubules were dissolved. Renal NO, NOS, SOD and eNOS levels decreased and MDA levels increased, renal E-selectin, VCAM-1and ICAM-1 protein levels increased in the TCE sensitization positive group and the TCE+Tempol sensitization positive group. Tempol attenuated TCE induced up-regulation of MDA, E-selectin, VCAM-1and ICAM-1 and down-regulation of NO, NOS, SOD and eNOS. In conclusion, trichloroethylene-sensitized mice renal immune injury is associated with the renal endothelial cells' oxidative stress state.


Assuntos
Células Endoteliais/efeitos dos fármacos , Haptenos/toxicidade , Nefropatias/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Solventes/toxicidade , Tricloroetileno/toxicidade , Animais , Antioxidantes/farmacologia , Óxidos N-Cíclicos/farmacologia , Dermatite Alérgica de Contato/metabolismo , Dermatite Alérgica de Contato/patologia , Selectina E/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Molécula 1 de Adesão Intercelular/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Malondialdeído/metabolismo , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Marcadores de Spin , Superóxido Dismutase/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
18.
J Mol Histol ; 50(3): 239-251, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049798

RESUMO

Reduced expression of endothelial nitric oxide synthase (eNOS) is a hallmark of endothelial dysfunction in diabetes, which predisposes diabetic patients to numerous cardiovascular complications including blunted angiogenesis. The Krüppel-like factor (KLF) five has been implicated as a central regulator of cardiovascular remodeling, but its role in endothelial cells (ECs) remains poorly understood. We show here that expression of endothelial KLF5 was significantly increased in the ECs from mouse diabetes mellitus type 2 (T2DM) model, when compared to non-diabetic or T1DM mouse. KLF5 up-regulation by insulin was dependent on activation of multiple pathways, including mammalian target of rapamycin, oxidative stress and Protein kinase C pathways. Hyperinsulinemia-induced KLF5 inhibited endothelial function and migration, and thereby compromised in vitro and in vivo angiogenesis. Mechanistically, KLF5 acted in concert with the MTA1 coregulator to negatively regulate NOS3 transcription, thereby leading to the diminished eNOS levels in ECs. Conversely, potentiation of cGMP content (the essential downstream effector of eNOS signaling) by pharmacological approaches successfully rescued the endothelial proliferation and in vitro tube formation, in the HUVECs overexpressing the exogenous KLF5. Collectively, the available data suggest that the augmentation of endothelial KLF5 expression by hyperinsulinemia may represent a novel mechanism for negatively regulating eNOS expression, and may thus help to explain for the T2DM-related endothelial dysfunction at the transcriptional level.


Assuntos
Hiperinsulinismo/genética , Fatores de Transcrição Kruppel-Like/genética , Neovascularização Patológica/genética , Óxido Nítrico Sintase Tipo III/genética , Animais , Movimento Celular/genética , Proliferação de Células/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperinsulinismo/patologia , Masculino , Camundongos , Estresse Oxidativo/genética , Proteína Quinase C/genética , Transdução de Sinais/genética
19.
Invest Ophthalmol Vis Sci ; 60(6): 1943-1952, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050722

RESUMO

Purpose: Ocular angiogenesis, including retinopathy of prematurity, diabetic retinopathy, and exudative age-related macular degeneration, are closely related to oxidative stress. Many reports have shown that the cellular protective mechanism against oxidative stress and inflammatory response has nuclear factor-erythroid 2-related factor-2 (Nrf2) activity. The aim of this study was to investigate the effectiveness and mechanism of Nrf2 activation in treating the ocular diseases with abnormal vessels. Methods: The effects of Nrf2 activators, bardoxolone methyl (BARD) and RS9, were evaluated against vascular endothelial growth factor (VEGF)-induced cell migration in human retinal microvascular endothelial cells (HRMECs). We measured the expression of the Nrf2 target genes, Ho-1 and Nqo-1 mRNA, in mouse retinas after a single injection of BARD and RS9. The effects and mechanisms of RS9 against retinal angiogenesis were evaluated using an oxygen-induced retinopathy (OIR) model in mice. Moreover, the effect of RS9 against choroidal neovascularization (CNV) was evaluated in a laser-induced CNV monkey model. Results: Both BARD and RS9 decreased VEGF-induced cell migration, and significantly increased Ho-1 mRNA expression; however, only RS9 significantly increased Nqo-1 mRNA. RS9 decreased retinal neovascularization through suppressing VEGF expression and increasing Nrf2, HO-1, platelet-derived growth factor receptor (PDGFR)-ß, and tight junction proteins in OIR murine retinas. Furthermore, RS9 showed a tendency toward decreasing CNV lesions, and improved vascular leakage in a CNV monkey model. Conclusions: These data indicate that a Nrf2 activator might be a candidate for treatment of ocular diseases characterized by pathophysiological angiogenesis and hyperpermeability.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleanólico/análogos & derivados , Neovascularização Retiniana/tratamento farmacológico , Vasos Retinianos/metabolismo , Triterpenos/farmacologia , Animais , Permeabilidade da Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Angiofluoresceinografia , Fundo de Olho , Humanos , Immunoblotting , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Ácido Oleanólico/farmacologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/patologia , Tomografia de Coerência Óptica
20.
Korean J Parasitol ; 57(2): 117-125, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31104403

RESUMO

Malarial infection induces tissue hypoxia in the host through destruction of red blood cells. Tissue hypoxia in malarial infection may increase the activity of HIF1α through an intracellular oxygen-sensing pathway. Activation of HIF1α may also induce vascular endothelial growth factor (VEGF) to trigger angiogenesis. To investigate whether malarial infection actually generates hypoxia-induced angiogenesis, we analyzed severity of hypoxia, the expression of hypoxia-related angiogenic factors, and numbers of blood vessels in various tissues infected with Plasmodium berghei. Infection in mice was performed by intraperitoneal injection of 2×106 parasitized red blood cells. After infection, we studied parasitemia and survival. We analyzed hypoxia, numbers of blood vessels, and expression of hypoxia-related angiogenic factors including VEGF and HIF1α. We used Western blot, immunofluorescence, and immunohistochemistry to analyze various tissues from Plasmodium berghei-infected mice. In malaria-infected mice, parasitemia was increased over the duration of infection and directly associated with mortality rate. Expression of VEGF and HIF1α increased with the parasitemia in various tissues. Additionally, numbers of blood vessels significantly increased in each tissue type of the malaria-infected group compared to the uninfected control group. These results suggest that malarial infection in mice activates hypoxia-induced angiogenesis by stimulation of HIF1α and VEGF in various tissues.


Assuntos
Células Endoteliais/patologia , Hipóxia , Malária/patologia , Neovascularização Patológica , Plasmodium berghei/crescimento & desenvolvimento , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Imuno-Histoquímica , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Parasitemia/parasitologia , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/análise
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA