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1.
Genet Res (Camb) ; 2022: 9129960, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35645613

RESUMO

Objectives: Endothelin-1 (ET-1), the most potent endogenous vasoconstrictor, generated by enzymatic cleavage catalyzed by an endothelin-converting enzyme (ECE), plays a significant role in the regulation of hypertension. Methods: This study investigates the effect of endothelin-1 (Lys198Asn/rs5370) and ECE (rs212526 C/T) gene polymorphisms with essential hypertension (EH) among Malay ethnics. To determine the association of gene polymorphism, 177 hypertensives and controls (196) were genotyped using Taqman method. Results: A significant difference was observed in ET-1 rs5370 and ECE rs212526 gene polymorphisms between EH and control subjects (P < 0.001). A significantly high body mass index (BMI), waist-to-hip ratio, fasting plasma glucose, hemoglobin A1c, systolic and diastolic blood pressure, and lipid profiles were observed among the EH patients when compared to controls (P < 0.05). Moreover, T allele (rs5370) carriers in males have a high risk for EH. There was no significant association between gender in ECE C/T polymorphisms (P > 0.05). Conclusion: Based on our result, it is evident that the T allele of ET-1 rs5370 polymorphism and C allele of ECE rs212526 have a significant genetic risk factor in EH among Malay subjects, and BMI and age are associated with hypertension.


Assuntos
Endotelina-1 , Enzimas Conversoras de Endotelina , Hipertensão Essencial , Endotelina-1/genética , Enzimas Conversoras de Endotelina/genética , Hipertensão Essencial/genética , Feminino , Humanos , Malásia/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único
2.
Dis Markers ; 2022: 6412238, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35178130

RESUMO

Lung transplantation requires optimization of donor's organ use through ex vivo lung perfusion (EVLP) to avoid primary graft dysfunction. Biomarkers can aid in organ selection by providing early evidence of suboptimal lungs during EVLP and thus avoid high-risk transplantations. However, predictive biomarkers of pulmonary graft function such as endothelin-converting enzyme (ECE-1) and vascular endothelial growth factor (VEGF) have not been described under EVLP with standard prolonged hypothermic preservation, which are relevant in situations where lung procurement is difficult or far from the transplantation site. Therefore, this study is aimed at quantifying ECE-1 and VEGF, as well as determining their association with hemodynamic, gasometric, and mechanical ventilatory parameters in a swine model of EVLP with standard prolonged hypothermic preservation. Using a protocol with either immediate (I-) or delayed (D-) initiation of EVLP, ECE-1 levels over time were found to remain constant in both study groups (p > 0.05 RM-ANOVA), while the VEGF protein was higher after prolonged preservation, but it decreased throughout EVLP (p > 0.05 RM-ANOVA). Likewise, hemodynamic, gasometric, mechanical ventilatory, and histological parameters had a tendency to better results after 12 hours of hypothermic preservation in the delayed infusion group.


Assuntos
Enzimas Conversoras de Endotelina/análise , Circulação Extracorpórea/métodos , Hipotermia Induzida , Fator A de Crescimento do Endotélio Vascular/análise , Animais , Biomarcadores/análise , Hipotermia Induzida/métodos , Pulmão/fisiologia , Pulmão/cirurgia , Transplante de Pulmão , Preservação de Órgãos/métodos , Suínos , Fatores de Tempo
3.
Biomed Res Int ; 2021: 7396580, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34532504

RESUMO

Endothelin is a chemical mediator that helps in maintaining balance within the blood-brain barrier by regulating the levels of toxicants and molecules which pass through the brain, suggesting that a rise in its production determines Alzheimer's disease. The inequity in the amyloid ß occurs due to a problem in its clearance from the brain initiating the production of reactive oxygen species and superoxide that activates a cascade wherein the release of inflammatory mediators and various enzymes like endothelin-converting enzymes take place. Furthermore, the cascade increases the levels of endothelin in the brain from endothelial cells. Endothelin levels are upregulated, which can be regulated by modulating the action of endothelin-converting enzymes and endothelin receptors. Hence, endothelin paves a pathway in the treatment of Alzheimer's disease. In this article, we have covered various mechanisms and preclinical studies that support and direct endothelin involvement in the progression of Alzheimer's disease by using various search tools such as PubMed, Science Direct, and Medline. Conclusive outcome data were extracted that all together defy contrivance pathways, potential drugs, endothelin receptors, and endothelin enzymes in our article giving profound importance to target endothelin for prevention and treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer/terapia , Endotelinas/efeitos dos fármacos , Endotelinas/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Enzimas Conversoras de Endotelina/metabolismo , Humanos , Neprilisina/genética
4.
Biochemistry (Mosc) ; 86(6): 680-692, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225591

RESUMO

The incidence of Alzheimer's disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic amyloid species and brain damage. The effects of global 15-min ischemia and 120-min reperfusion on the levels of expression of the amyloid precursor protein (APP) and its processing were investigated in the brain cortex (Cx) of male Wistar rats. Additionally, the levels of expression of the amyloid-degrading enzymes neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), and insulin-degrading enzyme (IDE), as well as of some markers of oxidative damage were assessed. It was shown that the APP mRNA and protein levels in the rat Cx were significantly increased after the ischemic insult. Protein levels of the soluble APP fragments, especially of sAPPß produced by ß-secretase, (BACE-1) and the levels of BACE-1 mRNA and protein expression itself were also increased after ischemia. The protein levels of APP and BACE-1 in the Cx returned to the control values after 120-min reperfusion. The levels of NEP and ECE-1 mRNA also decreased after ischemia, which correlated with the decreased protein levels of these enzymes. However, we have not observed any changes in the protein levels of insulin-degrading enzyme. Contents of the markers of oxidative damage (di-tyrosine and lysine conjugates with lipid peroxidation products) were also increased after ischemia. The obtained data suggest that ischemia shifts APP processing towards the amyloidogenic ß-secretase pathway and accumulation of the neurotoxic Aß peptide as well as triggers oxidative stress in the cells. These results are discussed in the context of the role of stress and ischemia in initiation and progression of AD.


Assuntos
Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Isquemia Encefálica/metabolismo , Córtex Cerebral/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/enzimologia , Córtex Cerebral/enzimologia , Enzimas Conversoras de Endotelina/genética , Enzimas Conversoras de Endotelina/metabolismo , Regulação da Expressão Gênica , Insulisina/genética , Insulisina/metabolismo , Masculino , Neprilisina/genética , Neprilisina/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo
5.
Bull Exp Biol Med ; 171(2): 194-197, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34173092

RESUMO

Restenosis remains the main complication after percutaneous coronary interventions in patients with coronary heart disease. The causes of its development include, in particular, genetic factors. We studied polymorphic loci of genes encoding endothelin-1 (EDN1 rs5370), endothelin-1 receptor (EDNRA rs5333), endothelin-converting enzyme (ECE1 rs1076669), and endothelial NO synthase (eNOS rs1549758, eNOS rs1799983, and eNOS rs2070244) in the context of in-stent restenosis development. It was found that the analyzed polymorphisms of the endothelin system genes were more significant for patients aged ≥ 65 years, while the polymorphic loci of the endothelial NO synthase gene (eNOS rs1799983 and eNOS rs1549758) were predominantly associated with time of in-stent restenosis. The obtained results can be useful for comprehensive assessment of the restenosis risk factors and the choice of optimal treatment for patients with coronary heart disease before elective surgical intervention.


Assuntos
Doença da Artéria Coronariana , Oclusão de Enxerto Vascular/genética , Intervenção Coronária Percutânea/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Vasos Coronários/cirurgia , Endotelina-1/genética , Enzimas Conversoras de Endotelina/genética , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Oclusão de Enxerto Vascular/epidemiologia , Humanos , Masculino , Neovascularização Patológica/epidemiologia , Neovascularização Patológica/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/genética , Receptor de Endotelina A/genética , Stents/efeitos adversos
6.
Endocr Regul ; 55(2): 72-82, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020533

RESUMO

Objective. The aim of the present investigation was to study the impact of glucose and gluta-mine deprivations on the expression of genes encoding EDN1 (endothelin-1), its cognate receptors (EDNRA and EDNRB), and ECE1 (endothelin converting enzyme 1) in U87 glioma cells in response to knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1), a major signaling pathway of endoplasmic reticulum stress, for evaluation of their possible implication in the control of glioma growth through ERN1 and nutrient limitations. Methods. The expression level of EDN1, its receptors and converting enzyme 1 in control U87 glioma cells and cells with knockdown of ERN1 treated by glucose or glutamine deprivation by quantitative polymerase chain reaction was studied. Results. We showed that the expression level of EDN1 and ECE1 genes was significantly up-regulated in control U87 glioma cells exposure under glucose deprivation condition in comparison with the glioma cells, growing in regular glucose containing medium. We also observed up-regulation of ECE1 gene expression in U87 glioma cells exposure under glutamine deprivation as well as down-regulation of the expression of EDN1 and EDNRA mRNA, being more significant for EDN1. Furthermore, the knockdown of ERN1 signaling enzyme function significantly modified the response of most studied gene expressions to glucose and glutamine deprivation conditions. Thus, the ERN1 knockdown led to a strong suppression of EDN1 gene expression under glucose deprivation, but did not change the effect of glutamine deprivation on its expression. At the same time, the knockdown of ERN1 signaling introduced the sensitivity of EDNRB gene to both glucose and glutamine deprivations as well as completely removed the impact of glucose deprivation on the expression of ECE1 gene. Conclusions. The results of this study demonstrated that the expression of endothelin-1, its receptors, and ECE1 genes is preferentially sensitive to glucose and glutamine deprivations in gene specific manner and that knockdown of ERN1 significantly modified the expression of EDN1, EDNRB, and ECE1 genes in U87 glioma cells. It is possible that the observed changes in the expression of studied genes under nutrient deprivation may contribute to the suppressive effect of ERN1 knockdown on glioma cell proliferation and invasiveness.


Assuntos
Endorribonucleases/metabolismo , Endotelina-1/metabolismo , Enzimas Conversoras de Endotelina/metabolismo , Glioma/metabolismo , Glucose/metabolismo , Glutamina/metabolismo , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Linhagem Celular Tumoral , Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , RNA Mensageiro/metabolismo
7.
Transl Res ; 235: 32-47, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33711514

RESUMO

Iodinated contrast is used for imaging and invasive procedures and it can cause contrast induced acute kidney injury (CI-AKI), which is the third leading hospital-acquired health problem. The purpose of the present study was to determine the effect of α-adrenergic receptor-1b (Adra1b) inhibition by using terazosin on change in kidney function, gene, and protein expression in C57BL/6J male mice, 6-8 weeks with chronic kidney disease (CKD). CKD was induced by surgical nephrectomy. Twenty eight days later, 100-µL of iodinated contrast (CI group) or saline (S group) was given via the carotid artery. Whole-transcriptome RNA-sequencing (RNA-Seq) analysis of the kidneys was performed at day 2. Mice received either 50-µL of saline ip or terazosin (2 mg/kg) in 50-µL of saline ip 1 hour before contrast administration which was continued every 12 hours until the animals were euthanized 2 and 7 days later. The kidneys were removed for gene expression, immunohistochemical analysis, and blood serum analyzed for kidney function. Differential gene expression analysis identified 21 upregulated and 436 downregulated genes (fold change >2; P < 0.05) that were common to all sample (n = 3 for both contrast and saline). We identified Adra1b using bioinformatic analysis. Mice treated with terazosin had a significant decrease in serum creatinine, urinary Kim-1 levels, HIF-1α, apoptosis, and downstream Adrab1 genes including Ece1, Edn1, pMAPK14 with increased cell proliferation. Contrast exposure upregulated Adra1b gene expression in HK-2 cells. Inhibition of Adra1b with terazosin abrogated Ece1, Edn1, and contrast-induced Fsp-1, Mmp-2, Mmp-9 expression, and caspase-3/7 activity in HK-2 cells.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Meios de Contraste/toxicidade , Prazosina/análogos & derivados , Injúria Renal Aguda/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Enzimas Conversoras de Endotelina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 14 Ativada por Mitógeno/análise , Prazosina/uso terapêutico , Receptores Adrenérgicos alfa 1/genética
8.
Front Immunol ; 12: 600056, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628210

RESUMO

The cellular response to interferon (IFN) is essential for antiviral immunity, IFN-based therapy and IFN-related disease. The plasma membrane (PM) provides a critical interface between the cell and its environment, and is the initial portal of entry for viruses. Nonetheless, the effect of IFN on PM proteins is surprisingly poorly understood, and has not been systematically investigated in primary immune cells. Here, we use multiplexed proteomics to quantify IFNα2a-stimulated PM protein changes in primary human CD14+ monocytes and CD4+ T cells from five donors, quantifying 606 and 482 PM proteins respectively. Comparison of cell surface proteomes revealed a remarkable invariance between donors in the overall composition of the cell surface from each cell type, but a marked donor-to-donor variability in the effects of IFNα2a. Furthermore, whereas only 2.7% of quantified proteins were consistently upregulated by IFNα2a at the surface of CD4+ T cells, 6.8% of proteins were consistently upregulated in primary monocytes, suggesting that the magnitude of the IFNα2a response varies according to cell type. Among these differentially regulated proteins, we found the viral target Endothelin-converting enzyme 1 (ECE1) to be an IFNα2a-stimulated protein exclusively upregulated at the surface of CD4+ T cells. We therefore provide a comprehensive map of the cell surface of IFNα2a-stimulated primary human immune cells, including previously uncharacterized interferon stimulated genes (ISGs) and candidate antiviral factors.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Enzimas Conversoras de Endotelina/imunologia , Interferon-alfa/farmacologia , Monócitos/imunologia , Linfócitos T CD4-Positivos/citologia , Humanos , Monócitos/citologia , Proteômica
9.
Int J Mol Sci ; 21(21)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182425

RESUMO

The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking.


Assuntos
Endocitose/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Transporte Proteico/fisiologia , Animais , Linhagem Celular , Citoplasma/metabolismo , Endossomos/metabolismo , Endossomos/fisiologia , Enzimas Conversoras de Endotelina/metabolismo , Células HEK293 , Humanos , Ligantes , Camundongos
10.
Mol Cancer ; 19(1): 151, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-33106166

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor and has a poor prognosis. The potential involvement of circular RNAs (circRNAs) in OS progression remains unexplored. Here, we report that CircECE1, a circular RNA derived from human ECE1, plays a critical role in energy metabolism in OS. METHODS: The RIP chip sequence assay was performed to confirm CircECE1, through overexpression or knockdown of CircECE1 to verify its function in 143B and U2OS. RNA immunoprecipitation and immunoprecipitation were used to verify CircECE1's regulation of protein c-Myc and co- immunoprecipitation was used to verified the competitive binding relationship between CircECE1 and SPOP. The influence of CircECE1 on energy metabolism was evaluated by seahorse experiment, western blot, and immunohistochemistry. RESULTS: We found that CircECE1 is highly expressed in OS tissues and cells and that CircECE1 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo. Further, CircECE1 significantly promotes glucose metabolism in OS cells in vitro and in vivo. Mechanistically, CircECE1 interacts with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation. C-Myc inhibits thioredoxin binding protein (TXNIP) transcription and subsequently activates the Warburg effect. CONCLUSIONS: CircECE1 regulates the Warburg effect through the c-Myc/TXNIP axis. CircECE1 mediated signal transduction plays a important role in OS process and energy metabolism. These findings may identify novel targets for OS molecular therapy.


Assuntos
Neoplasias Ósseas/patologia , Enzimas Conversoras de Endotelina/genética , Metabolismo Energético , Regulação Neoplásica da Expressão Gênica , Osteossarcoma/secundário , Proteínas Proto-Oncogênicas c-myc/química , RNA Circular/genética , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Proliferação de Células , Humanos , Camundongos , Camundongos Nus , MicroRNAs , Osteossarcoma/genética , Osteossarcoma/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Life Sci ; 258: 118223, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768584

RESUMO

Kidney fibrosis is a common final pathway of chronic kidney diseases, which are characterized by renal architecture damage, inflammation, fibroblast expansion and myofibroblast formation. Endothelin converting enzyme-1 (ECE-1) contributes to activation of Endothelin-1 (ET-1), a potent vasoconstrictor and pro-fibrotic substance. This study elucidated the effect of ECE-1 knockout in kidney fibrosis model in mice in association of ET-1 downregulation. Kidney fibrosis was performed in ECE-1 knockout (ECE-1 KO) and vascular endothelial derived ET-1 KO (VEETKO) mice (2 months, 20-30 g, n = 30) and their wild type (WT) littermates using unilateral ureteral obstruction (UUO) procedure. Mice were euthanized on day-7 and day-14 after UUO. Histopathological analysis was conducted for fibrosis and tubular injury. Immunostainings were done to quantify macrophages (F4/80), fibroblasts (FSP-1) and myofibroblasts (α-SMA). Monocyte Chemoattractant Protein-1 (MCP-1), ECE-1 and preproET-1 (ppET-1) mRNA expression were quantified with qRT-PCR, while Transforming Growth Factor-ß1 (TGF-ß1) and α-SMA protein level were quantified with Western blot. ECE-1 KO mice demonstrated reduction of ECE-1 and ppET-1 mRNA expression, attenuation of kidney fibrosis, tubular injury, MCP-1 mRNA expression and macrophage number compared to WT. Double immunostaining revealed fibroblast to myofibroblast formation after UUO, while ECE-1 KO mice had significantly lower fibroblast number and myofibroblast formation compared to WT, which were associated with significantly lower TGF-ß1 and α-SMA protein levels in day-14 of UUO. VEETKO mice also demonstrated attenuation of ET-1 protein level, fibrosis and myofibroblast formation. In conclusion, ECE-1 knockout and ET-1 downregulation attenuated kidney fibrosis.


Assuntos
Regulação para Baixo/fisiologia , Endotelina-1/metabolismo , Enzimas Conversoras de Endotelina/deficiência , Rim/metabolismo , Animais , Enzimas Conversoras de Endotelina/genética , Fibrose , Rim/patologia , Masculino , Camundongos , Camundongos Knockout
12.
Pregnancy Hypertens ; 20: 108-110, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32278308

RESUMO

Endothelin-converting enzyme-1(ECE-1) is a key regulatory enzyme in the processing of endothelin-1 (ET-1). We quantified and localized ECE-1 in normal and preeclamptic placentas. Normal (n=6) and preeclamptic (n=6) placentas were serially sectioned for immunofluorescence (IF). Cell type specific markers identified endothelial, trophoblast, macrophage, smooth muscle, and fibroblast cells. Quantitative analyses were performed by western blot and ELISA. IF identified ECE-1 expression within the stroma and villous space. Cellular localization of ECE-1 was limited to endothelial membranes. There was significantly less ECE-1 in preeclamptic placentas, suggesting ECE-1 is important for proper regulation of ET-1 within the placenta.


Assuntos
Enzimas Conversoras de Endotelina/análise , Placenta/enzimologia , Pré-Eclâmpsia/enzimologia , Adulto , Biomarcadores/análise , Estudos de Casos e Controles , Vilosidades Coriônicas/enzimologia , Regulação para Baixo , Células Endoteliais/enzimologia , Feminino , Humanos , Pré-Eclâmpsia/diagnóstico , Gravidez , Células Estromais/enzimologia
13.
J Oral Pathol Med ; 49(9): 835-841, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32170981

RESUMO

Oral squamous cell carcinoma is associated with many known risk factors including tobacco smoking, chronic alcoholism, poor oral hygiene, unhealthy dietary habits and microbial infection. Previous studies have highlighted Candida albicans host tissue infection as a risk factor in the initiation and progression of oral cancer. C albicans invasion induces several cancerous hallmarks, such as activation of proto-oncogenes, induction of DNA damage and overexpression of inflammatory signalling pathways. However, the molecular mechanisms behind these responses remain unclear. A recently discovered fungal toxin peptide, candidalysin, has been reported as an essential molecule in epithelial damage and host recognition of C albicans infection. Candidalysin has a clear role in inflammasome activation and induction of cell damage. Several inflammatory molecules such as IL-6, IL-17, NLRP3 and GM-CSF have been linked to carcinogenesis. Candidalysin is encoded by the ECE1 gene, which has been linked to virulence factors of C albicans such as adhesion, biofilm formation and filamentation properties. This review discusses the recent epidemiological burden of oral cancer and highlights the significance of the ECE1 gene and the ECE1 protein breakdown product, candidalysin in oral malignancy. The immunological and molecular mechanisms behind oral malignancy induced by inflammation and the role of the toxic fungal peptide candidalysin in oral carcinogenesis are explored. With increasing evidence associating C albicans with oral carcinoma, identifying the possible fungal pathogenicity factors including the role of candidalysin can assist in efforts to understand the link between C albicans infection and carcinogenesis, and pave the way for research into therapeutic potentials.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Candida albicans/genética , Carcinogênese/genética , Enzimas Conversoras de Endotelina , Proteínas Fúngicas , Humanos , Neoplasias Bucais/genética
14.
Mol Genet Genomic Med ; 8(4): e1188, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32107880

RESUMO

BACKGROUND: The ECE1 gene polymorphisms have been studied as a candidate gene in essential hypertension, but no consensus has been reached. To systematically explore their possible association, a case-control study was conducted. METHODS: This study included 398 hypertensive subjects and 596 healthy volunteers as control subjects in the Northern Han Chinese. A total of 10 tag SNPs of ECE1 gene were genotyped successfully by TaqMan assay. RESULTS: A total of 10 SNPs (rs212544, rs2076280, rs115071, rs2076283, rs9426748, rs11590928, rs212515, rs2236847, rs2282715, and rs2774028) were identified as the tag SNPs for ECE1 gene. Although no positive connection has been found in general population, several SNPs have been found to be related to EH risk in gender-stratified subgroup analysis. In males, rs115071 T allele influenced EH risk in a protective manner, with dominant model (TT+TC vs. CC: p = .032, OR = 0.655, 95% CI = 0.445-0.965), additive model (TT vs. TC vs. CC: p = .019, OR = 0.616, 95% CI = 0.411-0.924), as well as allele comparison (T vs. C: p = .045, OR = 0.702, 95% CI = 0.496-0.992). While, in females, rs212544 AA genotype would increase the onset risk of EH (recessive model: AA vs. GA+GG, p = .024, OR = 1.847, 95% CI = 1.086-3.142). In the three haplotype blocks identified, rs2076283-rs2236847 C-T haplotype was associated with a decreased risk of EH (OR = 0.558, p = .046). CONCLUSION: The current case-control study suggested that several SNPs and related haplotypes on ECE1 gene might be associated with the susceptibility of EH in certain gender subgroups in the Northern Han Chinese population.


Assuntos
Enzimas Conversoras de Endotelina/genética , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Idoso , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
JCI Insight ; 5(4)2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32102983

RESUMO

Accumulation of amyloid ß protein (Aß) due to increased generation and/or impaired degradation plays an important role in Alzheimer's disease (AD) pathogenesis. In this report, we describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (ECE2) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates ECE2 variants associated with the risk of developing AD. The 2 mutations (R186C and F751S) located in the peptidase domain in the ECE2 protein were found to severely impair the enzymatic activity of ECE2 in Aß degradation. We further evaluated the effect of the R186C mutation in mutant APP-knockin mice. Overexpression of wild-type ECE2 in the hippocampus reduced amyloid load and plaque formation, and improved learning and memory deficits in the AD model mice. However, the effect was abolished by the R186C mutation in ECE2. Taken together, the results demonstrated that ECE2 peptidase mutations contribute to AD pathogenesis by impairing Aß degradation, and overexpression of ECE2 alleviates AD phenotypes. This study indicates that ECE2 is a risk gene for AD development and pharmacological activation of ECE2 could be a promising strategy for AD treatment.


Assuntos
Doença de Alzheimer/genética , Encéfalo/metabolismo , Enzimas Conversoras de Endotelina/genética , Doença de Alzheimer/diagnóstico por imagem , Animais , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Estudos de Coortes , Modelos Animais de Doenças , Enzimas Conversoras de Endotelina/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Mutação , Linhagem
16.
Neoplasia ; 22(2): 98-110, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31923844

RESUMO

Endothelin-1 (ET-1) and its two receptors, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) exhibit deregulated overexprerssion in pancreatic ductal adenocarcinoma (PDAC) and pancreatitis. We examined the expression pattern of endothelin (ET) axis components in the murine models of chronic and acute inflammation in the presence or absence of oncogenic K-ras. While the expression of endothelin converting enzyme-1 (ECE-1), ET-1, ETAR and ETBR in the normal pancreas is restricted predominantly to the islet cells, progressive increase of ET receptors in ductal cells and stromal compartment is observed in the KC model (Pdx-1 Cre; K-rasG12D) of PDAC. In the murine pancreas harboring K-rasG12D mutation (KC mice), following acute inflammation induced by cerulein, increased ETAR and ETBR expression is observed in the amylase and CK19 double positive cells that represent cells undergoing pancreatic acinar to ductal metaplasia (ADM). As compared to the wild type (WT) mice, cerulein treatment in KC mice resulted in significantly higher levels of ECE-1, ET-1, ETAR and ETBR, transcripts in the pancreas. Similarly, in response to cigarette smoke-induced chronic inflammation, the expression of ET axis components is significantly upregulated in the pancreas of KC mice as compared to the WT mice. In addition to the expression in the precursor pancreatic intraepithelial neoplasm (PanIN lesions) in cigarette smoke-exposure model and metaplastic ducts in cerulein-treatment model, ETAR and ETBR expression is also observed in infiltrating F4/80 positive macrophages and α-SMA positive fibroblasts and high co-localization was seen in the presence of oncogenic K-ras. In conclusion, both chronic and acute pancreatic inflammation in the presence of oncogenic K-ras contribute to sustained upregulation of ET axis components in the ductal and stromal cells suggesting a potential role of ET axis in the initiation and progression of PDAC.


Assuntos
Endotelina-1/genética , Inflamação/genética , Neoplasias Pancreáticas/genética , Pancreatite/genética , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Amilases/genética , Animais , Ceruletídeo/toxicidade , Modelos Animais de Doenças , Enzimas Conversoras de Endotelina/genética , Regulação da Expressão Gênica/genética , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Camundongos , Oncogenes/genética , Neoplasias Pancreáticas/patologia , Pancreatite/induzido quimicamente , Pancreatite/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
17.
Mol Oncol ; 14(2): 347-362, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31788944

RESUMO

Endothelin-1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin-1 rely on its activation by endothelin-converting enzyme-1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness. The N terminus of ECE1c is phosphorylated by protein kinase CK2 (also known as casein kinase 2), and this enhances its stability and promotes invasiveness in colorectal cancer cells. However, it is not known how phosphorylation improves stability and why this is correlated with increased aggressiveness. We hypothesized that CK2 phosphorylation protects ECE1c from N-terminal ubiquitination and, consequently, from proteasomal degradation. Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1cK6R ) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib. Furthermore, colorectal cancer cells overexpressing ECE1cK6R displayed enhanced cancer stem cell (CSC) traits, including increased stemness gene expression, chemoresistance, self-renewal, and colony formation and spheroid formation in vitro, as well as enhanced tumor growth and metastasis in vivo. These findings suggest that CK2-dependent phosphorylation enhances ECE1c stability, promoting an increase in CSC-like traits. Therefore, phospho-ECE1c may be a biomarker of poor prognosis and a potential therapeutic target for colorectal cancer.


Assuntos
Carcinogênese/metabolismo , Neoplasias Colorretais/metabolismo , Enzimas Conversoras de Endotelina/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Carcinogênese/genética , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/genética , Caseína Quinase II/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Enzimas Conversoras de Endotelina/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Mutação , Naftiridinas/farmacologia , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Fenazinas/farmacologia , Fosforilação , Prognóstico , Estabilidade Proteica , Proteínas Recombinantes , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Hypertension ; 75(3): 877-884, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31884859

RESUMO

Increasing evidence suggests a role for the ET (endothelin) system in preeclampsia. Hence, blocking this system with endothelin receptor antagonists (ERAs) could be a therapeutic strategy. Yet, clinical studies are lacking due to possible teratogenic effects of ERAs. In this study, we investigated the placental transfer of ERAs and their effect on ET-1-mediated vasoconstriction. Term placentas were dually perfused with the selective ETAR (ET type A receptor) antagonists sitaxentan and ambrisentan or the nonselective ETAR/ETBR antagonist macitentan and subsequently exposed to ET-1 in the fetal circulation. ET-1 concentration-response curves after incubation with sitaxentan, ambrisentan, macitentan, or the selective ETBR antagonist BQ-788 were also constructed in isolated chorionic plate arteries using wire-myography, and gene expression of the ET-system was quantified in healthy and early onset preeclamptic placentas. At steady state, the mean fetal-to-maternal transfer ratios were 0.32±0.05 for sitaxentan, 0.21±0.02 for ambrisentan, and 0.05±0.01 for macitentan. Except for BQ-788, all ERAs lowered the response to ET-1, both in the perfused cotyledon and isolated chorionic plate arteries. Placental gene expression of ECE-1, ETAR, and ETBR were comparable in healthy and preeclamptic placentas, while ET-1 expression was higher in preeclampsia. Our study is the first to show direct transfer of ERAs across the term human placenta. Furthermore, ETAR exclusively mediates ET-1-induced constriction in the fetoplacental vasculature. Given its limited transfer, macitentan could be considered as potential preeclampsia therapy. Extending knowledge on placental transfer to placentas of preeclamptic pregnancies is required to determine whether ERAs might be applied safely in preeclampsia.


Assuntos
Antagonistas dos Receptores de Endotelina/farmacologia , Placenta/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Endotelina-1/biossíntese , Endotelina-1/sangue , Endotelina-1/genética , Enzimas Conversoras de Endotelina/biossíntese , Enzimas Conversoras de Endotelina/genética , Feminino , Transfusão Feto-Materna , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoxazóis/farmacologia , Oligopeptídeos/farmacologia , Fenilpropionatos/farmacologia , Piperidinas/farmacologia , Placenta/irrigação sanguínea , Placenta/metabolismo , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Piridazinas/farmacologia , Pirimidinas/farmacologia , Receptor de Endotelina A/biossíntese , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/genética , Receptor de Endotelina A/fisiologia , Receptor de Endotelina B/biossíntese , Receptor de Endotelina B/genética , Sulfonamidas/farmacologia , Tiofenos/farmacologia
19.
Neurocrit Care ; 33(1): 73-81, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595393

RESUMO

BACKGROUND: Our previous study found that mild hypothermia (MH) after resuscitation reduced cerebral microcirculation, but the mechanism was not elucidated. The aim of this study was to clarify changes of endothelin-1 (ET-1) and nitric oxide (NO) systems in brain tissue during hypothermia after resuscitation. METHODS: Twenty-six domestic male Beijing Landrace pigs were used in this study. MH was intravascularly induced 1 h after resuscitation from 8-min ventricular fibrillation. Core temperature was reduced to 33 °C and maintained until 8 h after resuscitation, and then animals were euthanized. ET-1 and NO levels in brain tissue and peripheral plasma were measured. Expression of endothelin-converting enzyme-1 (ECE-1), endothelin A receptor (ET-AR), endothelin-B receptor, and nitric oxide synthase (NOS) in brain tissue was determined by Western blot analysis. RESULTS: Compared with non-hypothermia (NH) treatment, MH after resuscitation significantly increased the level of endothelin-1 and reduced the level of NO in peripheral blood and brain tissue. Cerebral expression of ECE-1 and ET-AR was significantly increased during MH after resuscitation. Moreover, MH significantly decreased inducible NOS expression compared with the NH group. CONCLUSIONS: The ET-1 system is activated, while inducible NOS is inhibited in brain tissue during MH after resuscitation.


Assuntos
Encéfalo/metabolismo , Endotelina-1/metabolismo , Enzimas Conversoras de Endotelina/metabolismo , Parada Cardíaca/metabolismo , Hipotermia Induzida , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico/metabolismo , Receptores de Endotelina/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Masculino , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Sus scrofa , Suínos
20.
J Int Med Res ; 48(3): 300060519886987, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31777301

RESUMO

OBJECTIVE: Endothelin-1 (ET-1) promotes the progression and induction of sclerotic renal changes in end-stage kidney disease. Membrane-bound endothelin-converting enzyme 1 (ECE-1) is involved in the production of ET-1. The aim of this study was to assess the effects of ECE-1b rs213045 and rs2038089 polymorphisms, which have been shown to be involved in the development of atherosclerosis, hypertension, and nephropathy, on the development of contrast-induced acute kidney injury (CI-AKI) in patients with acute coronary syndrome. METHODS: Our study included 38 patients with CI-AKI (CI-AKI[+]) and 55 patients without CI-AKI (CI-AKI[-]) who had coronary syndrome. The ECE-1b polymorphisms rs213045 and rs2038089 were assessed using real-time PCR. Serum ET-1 levels were measured by ELISA. RESULTS: The distributions of ECE-1b rs213045 and rs2038089 polymorphisms were similar between the two groups. Additionally, the serum ET-1 level did not different between the groups and was not associated with the ECE-1b polymorphisms. Peri-procedural low systolic blood pressure (SBP) was identified as a risk factor for CI-AKI development. CONCLUSION: Our findings indicate that ECE-1b rs213045 and rs2038089 polymorphisms are not associated with CI-AKI development and that peri-procedural low SBP is a risk factor for CI-AKI. However, variations in ECE-1b rs2038089 may contribute to the development of CI-AKI.


Assuntos
Síndrome Coronariana Aguda , Injúria Renal Aguda , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/genética , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/complicações , Injúria Renal Aguda/genética , Ácido Aspártico Endopeptidases/genética , Meios de Contraste , Enzimas Conversoras de Endotelina , Humanos , Metaloendopeptidases/genética
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