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1.
Front Physiol ; 13: 954454, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36117702

RESUMO

Osteoarthritis (OA) is the most prevalent joint disease, characterized by the degradation of articular cartilage, synovial inflammation, and changes in periarticular and subchondral bone. Recent studies have reported that Wnt signaling cascades play an important role in the development, growth, and homeostasis of joints. The Wnt signaling cascade should be tightly regulated to maintain the homeostasis of cartilage in either the over-activation or the suppression of Wnt/ß-catenin, as this could lead to OA. This review summarizes the role and mechanism of canonical Wnt cascade and noncanonical Wnt cascade experiments in vivo and in vitro. The Wnt cascade is controlled by several agonists and antagonists in the extracellular medium and the cytoplasm. These antagonists and agonists serve as key molecules in drug intervention into the Wnt pathway and may provide potential approaches for the treatment of OA. However, the complexity of the Wnt signaling cascade and the pharmaceutical effects on its mechanism are still not fully understood, which forces us to conduct further research and develop efficient therapeutic approaches to treat OA.

2.
Front Endocrinol (Lausanne) ; 13: 919366, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36034459

RESUMO

Background: To investigate whether osteopontin (OPN) affects autophagy in human osteoarthritic chondrocytes and determine the roles of CD44, αvß3 integrin and the Mitogen-activated protein kinase (MAPK) pathway in this progress. Methods: First, we compared the autophagy levels in the human osteoarthritis (OA) and normal cartilage, then, we cultured human OA chondrocytes in vitro and treated cells with recombinant human OPN (rhOPN) to determine autophagy changes. Next, the anti-CD44 and anti-CD51/61 monoclonal antibodies (Abs) or isotype IgG were used to determine the possible role of CD44 and αvß3 integrin; subsequently, an inhibitor of the ERK MAPK pathway was used to investigate the role of ERK MAPK. Western blotting was used to measure the Beclin1, LC3 II and MAPK proteins expressions, mRFP-GFP-LC3 confocal imaging and transmission electron microscopy were also used to detect the autophagy levels. Cell Counting Kit-8 (CCK-8) was used to assay the proliferation and activity of chondrocytes. Results: The LC3 protein was greatly decreased in OA cartilage compared to normal cartilage, and OPN suppressed the autophagy activity in chondrocytes in vitro. Blocking experiments with anti-CD44 and anti-CD51/61 Abs indicated that OPN could suppress the expression of LC3II and Beclin1 through αvß3 integrin and CD44. Our results also indicated that the ratio of p-ERK/ERK but not p-P38/P38 and p-JNK/JNK was increased after the rhOPN treatment. The ERK inhibitor inhibited the activity of OPN in the suppression of autophagy, and the CCK-8 results showed that rhOPN could promote chondrocyte proliferation. Conclusion: OPN inhibited chondrocyte autophagy through CD44 and αvß3 integrin receptors and via the ERK MAPK signaling pathway.


Assuntos
Condrócitos , Osteoartrite , Autofagia , Proteína Beclina-1 , Humanos , Receptores de Hialuronatos , Integrinas , Proteínas Quinases Ativadas por Mitógeno , Osteopontina , Sincalida
3.
Arthritis Res Ther ; 24(1): 165, 2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-35804467

RESUMO

BACKGROUND: Dietary magnesium deficiency, which is common in modern diet, has been associated with osteoarthritis (OA) susceptibility. Despite this clinical association, no study has addressed if dietary magnesium deficiency accelerates OA development, especially at molecular level. This study aimed to explore aggravating effects of dietary magnesium deficiency on cartilage damage in an injury-induced murine OA model and to determine the underlying mechanism. METHODS: Twelve-week-old C57BL/6J mice subject to injury-induced OA modeling were randomized into different diet groups in which the mice were fed a diet with daily recommended magnesium content (500 mg/kg) or diets with low magnesium content (100 or 300 mg/kg). Articular cartilage damage was evaluated using the OARSI score. To determine molecular mechanisms in vitro, mouse chondrocytes were treated with media of low magnesium conditions at 0.1 and 0.4 mM, compared with normal magnesium condition at 0.7 mM as control. Anabolic and catabolic factors, autophagy markers, ß-catenin, Wnt ligands, and a magnesium channel transient receptor potential cation channel subfamily member 7 (TRPM7) were analyzed by quantitative real-time PCR and immunoblotting. Autolysosomes were detected by DALGreen staining via fluorescence microscopy and autophagosomes were evaluated by transmission electron microscopy. Autophagy markers, ß-catenin, and TRPM7 were assessed in vivo in the mouse cartilage, comparing between dietary magnesium deficiency and normal diet, by immunohistochemistry. RESULTS: Dietary magnesium deficiency aggravated injury-induced cartilage damage, indicated by significant higher OARSI scores. Autophagy markers LC3-II and Beclin-1 were decreased both in low magnesium diet-fed mice and low magnesium-treated chondrocytes. The number of autolysosomes and autophagosomes was also reduced under low magnesium conditions. Moreover, magnesium deficiency induced decreased anabolic and increased catabolic effect of chondrocytes which could be restored by autophagy activator rapamycin. In addition, reduced autophagy under low magnesium conditions is mediated by activated Wnt/ß-catenin signaling. The expression of TRPM7 also decreased in low magnesium diet-fed mice, indicating that downstream changes could be regulated through this channel. CONCLUSIONS: Dietary magnesium deficiency contributes to OA development, which is mediated by reduced autophagy through Wnt/ß-catenin signaling activation. These findings indicated potential benefits of adequate dietary magnesium for OA patients or those individuals at high risk of OA.


Assuntos
Cartilagem Articular , Deficiência de Magnésio , Osteoartrite , Canais de Cátion TRPM , Animais , Autofagia , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Magnésio/farmacologia , Deficiência de Magnésio/complicações , Deficiência de Magnésio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Canais de Cátion TRPM/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismo
4.
ACS Appl Mater Interfaces ; 14(1): 1478-1488, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-34928125

RESUMO

Transparent flexible supercapacitors (TFSCs) are a tantalizing power supplier for future transparent flexible electronics. However, their energy density is far behind a practical level while maintaining high transparency. We report here a transparent flexible potassium-ion microcapacitor, and its high energy density (15.5 µWh cm-2) roots in the battery-supercapacitor hybrid storage mechanism and much enlarged working voltage (3 V), outperforming the state-of-the-art TFSC, which is generally based on an aqueous electrolyte and an asymmetric pseudocapacitive mechanism. From an electrode material perspective, a multidimensional topotactic host composite anode is designed in which the component not only performs energy storage by synchronous and reversible uptake of potassium ions and electrons into its host structure, but also mutually compensates individual weakness in functional and structural aspects, efficiently constructing a three-dimensional potassium-ion diffusion and electron transport system. This conceptual exhibition provides design principles at material and device levels for high-performance TFSCs.

5.
Nat Commun ; 6: 10068, 2015 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-26632666

RESUMO

PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficient mice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.


Assuntos
Neoplasias Encefálicas/enzimologia , Glioblastoma/enzimologia , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neurais/enzimologia , PTEN Fosfo-Hidrolase/deficiência , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Silenciamento de Genes , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/citologia , Células-Tronco Neurais/citologia , PTEN Fosfo-Hidrolase/genética , Fenótipo
6.
Science ; 348(6239): 1160-3, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25931448

RESUMO

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2ß. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.


Assuntos
Envelhecimento/metabolismo , Senescência Celular , Exodesoxirribonucleases/metabolismo , Heterocromatina/metabolismo , Células-Tronco Mesenquimais/metabolismo , RecQ Helicases/metabolismo , Síndrome de Werner/metabolismo , Envelhecimento/genética , Animais , Diferenciação Celular , Centrômero/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Exodesoxirribonucleases/genética , Técnicas de Inativação de Genes , Células HEK293 , Heterocromatina/química , Humanos , Proteínas de Membrana/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Modelos Biológicos , RecQ Helicases/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Síndrome de Werner/genética , Helicase da Síndrome de Werner
9.
Protein Cell ; 4(10): 723-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24104390

RESUMO

Hannum and colleagues performed DNA methylation sequencing to examine the relationship between DNA methylome and aging rate. Notably, they succeeded in building a quantitative and reproducible model based on the epigenetic bio-markers to predict aging rate with high accuracy. This progress enlightens us in many aspects particularly in applying this novel set of bio-markers on studying the mechanism of aging rate using adult tissue-specific stem cells, building up a potential quantitative model to explore the mechanism for other epigenetic factors like non-coding RNA, and understanding the principle and mechanism of 3D chromatin structure in epigenetic modulation.


Assuntos
Envelhecimento/genética , Cromatina/genética , Metilação de DNA/genética , Epigênese Genética , Envelhecimento/patologia , Sequência de Bases , Genoma Humano , Humanos , RNA não Traduzido/genética , Análise de Sequência de DNA/tendências
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