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1.
Nat Commun ; 7: 13710, 2016 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-27966531

RESUMO

Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen-Lysyl oxidase-like 2 (Loxl2)-is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-ß2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-ß2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.


Assuntos
Aminoácido Oxirredutases/fisiologia , Insuficiência Cardíaca/metabolismo , Miocárdio/patologia , Aminoácido Oxirredutases/sangue , Aminoácido Oxirredutases/metabolismo , Animais , Fibrose/metabolismo , Humanos , Camundongos Knockout , Miocárdio/metabolismo , Estresse Fisiológico
2.
J Exerc Nutrition Biochem ; 19(3): 191-7, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26527209

RESUMO

The present study demonstrates that prolonged restraint administration for 21 days caused memory impairment and induced hippocampal endoplasmic reticulum (ER) stress-mediated apoptosis. On the contrary, this change was revered by treadmill running for 8 weeks. Repeated psychological stress caused an increase in escape latency time in the water maze test, accompanied by the induction of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and cleaved/active caspase-12 protein in the hippocampus. The expression pattern of ER stress response-related proteins were counter-regulated by chronic exercise, as indicated by a reduction in GRP78, CHOP, and cleaved caspase-12, along with a decrease in escape latency time. In addition, the hippocampal expression pattern of phospho-cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) opposed that of ER stress response components. Accordingly, chronic exercise may attenuate prolonged stress-induced hippocampal ER stress and memory deficit, likely through CREB/BDNF signaling.

3.
Chin J Integr Med ; 20(9): 706-11, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23263996

RESUMO

OBJECTIVE: To identify the position of traditional herbal medicine in dementia research field using mapping technology. METHODS: Keywords for dementia and traditional herbal medicine for treating dementia were used to extract scientific articles from the Web of Science database from January 2000 to July 2010. A co-occurrence matrix was created based on the concurrent set of author's keywords occurring in each scientific article, and technology network maps were created from similarity index matrices. RESULTS: Twenty specialized research areas were identified in the dementia field, and the relationship strength was 0.2-0.6. Many research fields were associated with diagnosis and risk factors for dementia. Additionally, the mechanism or cause of dementia is an actively studied field. Traditional herbal medicine for treating dementia was located on a map near the cortical dementia diagnosis and therapy, and frontotemporal dementia research field with a relationship strength of 0.53 and 0.31-0.33 respectively, which demonstrates that traditional herbal medicine for dementia occupies an independent research area with a relationship to existing scientific research fields. CONCLUSION: Traditional herbal medicine can provide an alternative and complementary approach for treating dementia as evidenced by a scientific mapping analysis.


Assuntos
Pesquisa Biomédica , Demência/terapia , Medicina Herbária , Humanos
4.
Trends Cell Biol ; 19(8): 385-94, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19648010

RESUMO

Transforming growth factor-beta (TGF-beta) regulates cell proliferation, differentiation and apoptosis, and TGF-beta-related proteins have key roles in development, tissue homeostasis and disease. Upon binding to their cell surface receptors, TGF-beta family proteins signal through Smads to induce changes in gene expression. TGF-beta-induced Smad signaling and additional non-Smad pathways have been studied extensively in an effort to understand the complex and versatile responses to TGF-beta family proteins. Recently, it has become increasingly apparent that the signaling responses are also extensively defined by regulatory mechanisms at the level of the receptors themselves. Here, we discuss recent insights into the effects of post-translational modifications, protein associations and mode of internalization on the functions of the TGF-beta receptors and their signaling responses.


Assuntos
Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , Processamento de Proteína Pós-Traducional/fisiologia , Transdução de Sinais/fisiologia
5.
Nat Cell Biol ; 10(6): 654-64, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18469808

RESUMO

Post-translational sumoylation, the covalent attachment of a small ubiquitin-like modifier (SUMO), regulates the functions of proteins engaged in diverse processes. Often associated with nuclear and perinuclear proteins, such as transcription factors, it is not known whether SUMO can conjugate to cell-surface receptors for growth factors to regulate their functions. Here we show that the type I transforming growth factor-beta (TGF-beta) receptor, T beta RI, is sumoylated in response to TGF-beta and that its sumoylation requires the kinase activities of both T beta RI and the type II TGF-beta receptor, T beta RII. Sumoylation of T beta RI enhances receptor function by facilitating the recruitment and phosphorylation of Smad3, consequently regulating TGF-beta-induced transcription and growth inhibition. T beta RI sumoylation modulates the dissemination of transformed cells in a mouse model of T beta RI-stimulated metastasis. T beta RI sumoylation therefore controls responsiveness to TGF-beta, with implications for tumour progression. Sumoylation of cell-surface receptors may regulate other growth factor responses.


Assuntos
Regulação da Expressão Gênica , Proteínas Serina-Treonina Quinases/fisiologia , Receptores de Fatores de Crescimento Transformadores beta/fisiologia , Proteína SUMO-1/metabolismo , Animais , Células COS , Chlorocebus aethiops , Citoplasma/metabolismo , Humanos , Lisina/química , Camundongos , Modelos Biológicos , Metástase Neoplásica , Fosforilação , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta/metabolismo
6.
Biochem J ; 403(1): 177-82, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17176251

RESUMO

Rapid progress in the ability to develop and utilize zinc-finger proteins with customized sequence specificity have led to their increasing use as tools for modulation of target gene transcription in the post-genomic era. In the present paper, a series of in vitro binding assays and in vivo reporter analyses were used to demonstrate that a zinc-finger protein can effectively specify a base at each position of the target site in vivo and that functional activity of the zinc-finger protein as either a transcriptional repressor or activator is positively correlated with its binding affinity. In addition, this correlation can be extended to artificial engineered zinc-finger proteins. These data suggest that the binding affinity of designer zinc-finger proteins with novel specificity might be a determinant for their ability to regulate transcription of a gene of interest.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Linhagem Celular , Proteína 1 de Resposta de Crescimento Precoce/genética , Genes Reporter , Humanos , Rim , Cinética , Luciferases/genética , Ligação Proteica , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/metabolismo , Transfecção
7.
EMBO J ; 24(14): 2543-55, 2005 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-15990875

RESUMO

Transforming growth factor-beta (TGF-beta) inhibits osteoblast differentiation through inhibition of the function of Runx2 (Cbfa1) by Smad3. The mechanism through which TGF-beta/Smad3 inhibits Runx2 function has not been characterized. We show that TGF-beta induces histone deacetylation, primarily of histone H4, at the osteocalcin promoter, which is repressed by TGF-beta, and that histone deacetylation is required for repression of Runx2 by TGF-beta. This repression occurs through the action of the class IIa histone deacetylases (HDAC)4 and 5, which are recruited through interaction with Smad3 to the Smad3/Runx2 complex at the Runx2-binding DNA sequence. Accordingly, HDAC4 or 5 is required for efficient TGF-beta-mediated inhibition of Runx2 function and is involved in osteoblast differentiation. Our results indicate that class IIa HDACs act as corepressors for TGF-beta/Smad3-mediated transcriptional repression of Runx2 function in differentiating osteoblasts and are cell-intrinsic regulators of osteoblast differentiation.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Histona Desacetilases/classificação , Histona Desacetilases/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/fisiologia , Transativadores/fisiologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Células COS , Chlorocebus aethiops , Subunidade alfa 1 de Fator de Ligação ao Core , Mesoderma/metabolismo , Camundongos , Células NIH 3T3 , Osteoblastos/metabolismo , Osteocalcina/genética , Regiões Promotoras Genéticas , Proteína Smad3
8.
EMBO J ; 23(7): 1557-66, 2004 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-15044954

RESUMO

Transforming growth factor beta (TGF-beta) inhibits myogenesis and associated gene expression. We previously reported that the TGF-beta signaling effector Smad3 mediates this inhibition, by interfering with the assembly of myogenic bHLH transcription factor heterodimers on E-box sequences in the regulatory regions of muscle-specific genes. We now show that TGF-beta-activated Smad3 suppresses the function of MEF2, a second class of essential myogenic factors. TGF-beta signaling through Smad3 represses myogenin expression independently of E-boxes, and prevents a tethered MyoD-E47 dimer to activate transcription indirectly through MEF2-binding sites. In addition, Smad3 interacts with MEF2C, which requires its MADS domain, and disrupts its association with the SRC-family coactivator GRIP-1, thus diminishing the transcription activity of MEF2C. Consistent with this physical displacement, TGF-beta signaling blocks the GRIP-1-induced redistribution of MEF2C to discrete nuclear subdomains in 10T1/2 cells, and the recruitment of GRIP-1 to the myogenin promoter in differentiating myoblasts. These findings indicate that the TGF-beta/Smad3 pathway targets two critical components of the myogenic transcription machinery to inhibit terminal differentiation.


Assuntos
Diferenciação Celular/fisiologia , Proteínas de Ligação a DNA/metabolismo , Células Musculares/fisiologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Fatores de Transcrição MEF2 , Células Musculares/citologia , Fatores de Regulação Miogênica , Coativador 2 de Receptor Nuclear , Regiões Promotoras Genéticas , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/fisiologia , Proteína Smad3 , Fatores de Transcrição/genética
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