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1.
Cell Metab ; 33(10): 2059-2075.e10, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34536344

RESUMO

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

2.
J Cell Biochem ; 120(10): 17337-17344, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31209945

RESUMO

Transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, promotes tumor progression by serving as a transcriptional coactivator with TEAD. Here, we introduced a new construct which can express the TEAD-binding domain of TAZ protein (TAZBD), and determined its antitumor effect in malignant glioma both in vitro and in vivo. We first observed that TAZ was upregulated in glioma tissues and related to malignant clinicopathologic characteristic, indicating the crucial role of TAZ during glioma progression. In U87 and U251 cells, TAZBD expression increased the proportion of apoptotic cells, and suppressed the colony formation and tumorigenicity. Further, TAZBD also decreased cell metastasis through the repression of epithelial-mesenchymal transition. The mechanistic study showed that TAZBD suppression of glioma cells was predominantly through blocking the TAZ-TEAD complex formation by competing with endogenous TAZ. Thus, the gene therapy of malignant glioma through blocking TAZ-TEAD complex by TAZBD may provide a new way for the targeted therapy of glioma.


Assuntos
Apoptose , Neoplasias Encefálicas/secundário , Proteínas de Ligação a DNA/metabolismo , Transição Epitelial-Mesenquimal , Glioma/patologia , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica , Proteínas Nucleares/genética , Prognóstico , Transativadores/genética , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Hepatology ; 70(5): 1750-1769, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31077413

RESUMO

Hepatic ischemia-reperfusion (IR) injury is the leading cause of liver dysfunction and failure after liver resection or transplantation and lacks effective therapeutic strategies. Here, we applied a systematic proteomic analysis to identify the prominent contributors to IR-induced liver damage and promising therapeutic targets for this condition. Based on an unbiased proteomic analysis, we found that toll-interacting protein (Tollip) expression was closely correlated with the hepatic IR process. RNA sequencing analysis and phenotypic examination showed a dramatically alleviated hepatic IR injury by Tollip deficiency both in vivo and in hepatocytes. Mechanistically, Tollip interacts with apoptosis signal-regulating kinase 1 (ASK1) and facilitates the recruitment of tumor necrosis factor receptor-associated factor 6 (TRAF6) to ASK1, leading to enhanced ASK1 N-terminal dimerization and the subsequent activation of downstream mitogen-activated protein kinase (MAPK) signaling. Furthermore, the Tollip methionine and phenylalanine motif and TRAF6 ubiquitinating activity are required for Tollip-regulated ASK1-MAPK axis activation. Conclusion: Tollip is a regulator of hepatic IR injury by facilitating ASK1 N-terminal dimerization and the resultant c-Jun N-terminal kinase/p38 signaling activation. Inhibiting Tollip or its interaction with ASK1 might be promising therapeutic strategies for hepatic IR injury.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Fígado/irrigação sanguínea , Proteômica , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
Nat Med ; 24(1): 73-83, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29227475

RESUMO

Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE-GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.


Assuntos
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Araquidonato 12-Lipoxigenase/metabolismo , Fígado/irrigação sanguínea , Receptores Acoplados a Proteínas G/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/antagonistas & inibidores , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/biossíntese , Animais , Modelos Animais de Doenças , Progressão da Doença , Humanos , Metabolismo dos Lipídeos , Camundongos , Traumatismo por Reperfusão/parasitologia , Suínos
5.
Brain Res ; 1336: 98-102, 2010 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-20388496

RESUMO

14-3-3 proteins comprise a large family of highly conserved, acidic polypeptides, expressed in all eukaryotic organisms, with highest concentration found in the brain. Multiple isoforms of 14-3-3 proteins have been shown to play an essential role in regulating differentiation, proliferation and transformation. In the previous study, the expression levels of all seven 14-3-3 isoforms were examined in astrocytoma. However, the expression of seven 14-3-3 isoforms in meningioma still remains unknown. This study is the first examination of 14-3-3 isoforms in three grades of meningioma by immunohistochemistry. 14-3-3epsilon, zeta and theta were specifically expressed in meningioma, and their expression levels increased with the increase of pathological grade of meningioma. The 14-3-3 eta, beta, gamma and sigma isoforms were negatively expressed in meningioma. In conclusion, The 14-3-3 epsilon, zeta and theta may be involved in tumorigenesis of meningioma and be efficient markers for predicting the degree of malignancy in meningioma.


Assuntos
Proteínas 14-3-3/biossíntese , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/patologia , Meningioma/metabolismo , Meningioma/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Isoformas de Proteínas/biossíntese , Adulto Jovem
6.
Brain Res ; 1304: 149-54, 2009 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-19782666

RESUMO

HIF-1alpha plays an indispensable role in tumor formation and histogenesis. Target genes involved in glucose transport are acutely transactivated by HIF-1alpha. GLUT-3 protein is the rate-limiting factor related to glucose transport, which is classified as brain-type glucose transporter. This study was the initial one aiming to probe into the co-expression and clinical significance of HIF-1alpha and GLUT-3 in glioma. One hundred and twenty cases of glioma tissues and ten human normal cerebral tissues decompressed in glioma excision were examined using immunohistochemistry and Western blot. The expression of HIF-1alpha and GLUT-3 increased gradually with the increase of pathological grade of glioma, respectively. There was significant difference in the expression of HIF-1alpha and GLUT-3 in every two groups, respectively. There was a positive correlation between HIF-1alpha and GLUT-3. In conclusion, the expression of HIF-1alpha and GLUT-3 in glioma was correlated significantly with tumors' pathological grade, which can be taken as a pair of useful markers for predicting the biological behavior of glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Glioma/metabolismo , Transportador de Glucose Tipo 3/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Actinas/metabolismo , Adolescente , Adulto , Idoso , Western Blotting , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Núcleo Celular/metabolismo , Criança , Feminino , Glioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Adulto Jovem
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