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1.
Cell Biol Int ; 48(11): 1625-1636, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39252384

RESUMEN

Lysosomes are involved in a myriad of cellular functions, such as degradation of macromolecules, endocytosis and exocytosis, modulation of several signaling pathways, and regulation of cell metabolism. To fulfill these diverse functions, lysosomes can undergo several dynamic changes in their content, size, pH, and location within cells. Here, we studied some of these parameters during embryonic chick skeletal muscle cells. We used an anti-lysosome-associated membrane protein 2 (LAMP2) antibody to specifically determine the intracellular localization of lysosomes in these cells. Our data shows that lysosomes are highly enriched in the perinuclear region of chick embryonic muscle cells. We also showed that the wingless signaling pathway (Wnt)/ß-catenin signaling pathway can modulate the location of LAMP2 in chick myogenic cells. Our results highlight the role of lysosomes during muscle differentiation and particularly the presence of a subcellular population of lysosomes that are concentrated in the perinuclear region of muscle cells.


Asunto(s)
Lisosomas , Desarrollo de Músculos , Animales , Lisosomas/metabolismo , Desarrollo de Músculos/fisiología , Embrión de Pollo , Diferenciación Celular/fisiología , Vía de Señalización Wnt/fisiología , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/citología , Núcleo Celular/metabolismo , Pollos , beta Catenina/metabolismo , Células Musculares/metabolismo , Células Musculares/citología , Células Cultivadas
2.
Psychiatry Res ; 339: 115983, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38870775

RESUMEN

Despite uncertainty about the specific molecular mechanisms driving major depressive disorder (MDD), the Wnt signaling pathway stands out as a potentially influential factor in the pathogenesis of MDD. Known for its role in intercellular communication, cell proliferation, and fate, Wnt signaling has been implicated in diverse biological phenomena associated with MDD, spanning neurodevelopmental to neurodegenerative processes. In this systematic review, we summarize the functional differences in protein and gene expression of the Wnt signaling pathway, and targeted genetic association studies, to provide an integrated synthesis of available human data examining Wnt signaling in MDD. Thirty-three studies evaluating protein expression (n = 15), gene expression (n = 9), or genetic associations (n = 9) were included. Only fifteen demonstrated a consistently low overall risk of bias in selection, comparability, and exposure. We found conflicting observations of limited and distinct Wnt signaling components across diverse tissue sources. These data do not demonstrate involvement of Wnt signaling dysregulation in MDD. Given the well-established role of Wnt signaling in antidepressant response, we propose that a more targeted and functional assessment of Wnt signaling is needed to understand its role in depression pathophysiology. Future studies should include more components, assess multiple tissues concurrently, and follow a standardized approach.


Asunto(s)
Trastorno Depresivo Mayor , Vía de Señalización Wnt , Humanos , Trastorno Depresivo Mayor/metabolismo , Vía de Señalización Wnt/fisiología
3.
Clin Transl Oncol ; 25(4): 976-986, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36463369

RESUMEN

PURPOSE: SMEK1, also known as PP4R3α, the regulatory subunit 3α of serine and threonine phosphatase PP4, participates in diversely critical biological processes such as the integration of centromere, deacetylation of histones, asymmetric divisions of neuroblast, and other crucial cellular activities. SMEK1 was formerly reported to play a part in carcinogenesis. This study aims to reveal the role of SMEK1 in lung adenocarcinoma and the underlying molecular mechanism. METHODS: Using immunohistochemical (IHC) staining, the protein level of SMEK1 in lung adenocarcinoma and adjacent non-tumor tissue was detected. The functional role of SMEK1 in cell proliferation and invasion was explored using cell counting kit-8 and Transwell assay, respectively. Xenograft tumor experiment was used to investigate the effect of SMEK1 on tumor growth in vivo. The alteration of Wnt/ß-catenin signaling pathway was detected by Western blotting, quantitative PCR, and dual-luciferase reporter assays. RESULTS: SMEK1 was highly expressed at the protein level in lung adenocarcinoma compared to the adjacent non-tumor tissue. In vitro, suppression of SMEK1 significantly decreased the proliferation, migration, and invasion of lung adenocarcinoma cell lines, while overexpression of SMEK1 enhanced above abilities. The xenograft model demonstrated that down-regulation of SMEK1 significantly inhibited tumor growth in vivo. In addition, we found that SMEK1 could positively regulate Wnt/ß-catenin signaling in lung adenocarcinoma cell lines. CONCLUSIONS: SMEK1 exerts a cancer-promoting effect in lung adenocarcinoma by activating Wnt/ß-catenin signaling.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Vía de Señalización Wnt/fisiología , Línea Celular Tumoral , beta Catenina/metabolismo , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Proliferación Celular , Movimiento Celular , Regulación Neoplásica de la Expresión Génica
4.
Exp Gerontol ; 165: 111854, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35642846

RESUMEN

Wnt signaling plays an important role in adult brain function, and its dysregulation has been implicated in functional decline during aging as well as in some neurodegenerative diseases, such as Alzheimer's disease. In the adult brain, the Wnt pathway contributes to synapse formation and maintenance, axonal remodeling, and dendrite outgrowth. Recent findings indicate a downregulation of Wnt signaling in the aged brain in different models, but it has not been associated with changes in the number and structure of central synapses. The expression and distribution of Wnt components in different brain regions may vary with age, which may have important implications for brain homeostasis manifesting as different behavioral alterations. Thus, in the present work, we analyzed the expression levels and protein content of different molecules of the Wnt pathway in young and aged rats in the cerebral cortex, hippocampus and cerebellum and discussed their correlation with changes in synaptic number and morphology.


Asunto(s)
Enfermedad de Alzheimer , Vía de Señalización Wnt , Enfermedad de Alzheimer/metabolismo , Animales , Hipocampo/metabolismo , Ratas , Sinapsis , Vía de Señalización Wnt/fisiología
5.
Stem Cells ; 40(7): 630-640, 2022 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-35446432

RESUMEN

The subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) is a neurogenic niche of the adult brain that contains neural stem cells (NSCs) able to generate excitatory glutamatergic granule neurons, which integrate into the DG circuit and contribute to hippocampal plasticity, learning, and memory. Thus, endogenous NSCs could be harnessed for therapeutic purposes. In this context, it is critical to characterize the molecular mechanisms controlling the generation and functional integration of adult-born neurons. Adult hippocampal neurogenesis is tightly controlled by both cell-autonomous mechanisms and the interaction with the complex niche microenvironment, which harbors the NSCs and provides the signals to support their maintenance, activation, and differentiation. Among niche-derived factors, Wnt ligands play diverse roles. Wnts are secreted glycoproteins that bind to Frizzled receptors and co-receptors to trigger the Wnt signaling pathway. Here, we summarize the current knowledge about the roles of Wnts in the regulation of adult hippocampal neurogenesis. We discuss the possible contribution of the different niche cells to the regulation of local Wnt signaling activity, and how Wnts derived from different cell types could induce differential effects. Finally, we discuss how the effects of Wnt signaling on hippocampal network activity might contribute to neurogenesis regulation. Although the evidence supports relevant roles for Wnt signaling in adult hippocampal neurogenesis, defining the cellular source and the mechanisms controlling secretion and diffusion of Wnts will be crucial to further understand Wnt signaling regulation of adult NSCs, and eventually, to propose this pathway as a therapeutic target to promote neurogenesis.


Asunto(s)
Células-Madre Neurales , Vía de Señalización Wnt , Adulto , Diferenciación Celular/fisiología , Hipocampo , Humanos , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Vía de Señalización Wnt/fisiología
6.
Clin Transl Oncol ; 24(3): 546-555, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35031966

RESUMEN

OBJECTIVE: Accumulating evidence has been revealed that miR-590 is involved in the progression and carcinogenesis of various cancers. However, the molecular mechanism of miR-590 in non-small-cell lung cancer (NSCLC) remains unclear. METHODS: Quantitative reverse transcription-PCR (qRT-PCR), western blot, MTT, and transwell assay were applied to investigate the functional role of miR-590 in this study. Dual luciferase reporter assay was utilized to investigate the interaction between YAP1 and miR-590 expression. Cells transfected with miR-590 mimic or inhibitor were subjected to western blot to investigate the role of Wnt/ß-catenin signaling in NSCLC modulated by miR-590. RESULTS: MiR-590 was down-regulated in NSCLC tissues and cells. Kaplan-Meier analysis found that the higher expression of miR-590 in NSCLC patients, the more improved survival rate of NSCLC patients. Over-expression of miR-590 inhibited NSCLC cell proliferation, migration, and invasion. Moreover, increasing miR-590 suppressed Yes-associated protein 1 (YAP1) expression and inhibited the Wnt/ß-catenin pathway in NSCLC cells. Furthermore, miR-590 was negatively correlated with YAP1 expression. CONCLUSION: These findings demonstrated that the miR-590/YAP1 axis exerted an important role in the progression of NSCLC, suggesting that miR-590 might be the appealing prognostic marker for NSCLC treatment.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , MicroARNs/fisiología , Vía de Señalización Wnt/fisiología , Proteínas Señalizadoras YAP/fisiología , Progresión de la Enfermedad , Humanos , Células Tumorales Cultivadas
7.
J Clin Endocrinol Metab ; 106(9): 2690-2706, 2021 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-33871626

RESUMEN

CONTEXT: Acromegaly can impair bone integrity, increasing the risk of vertebral fractures (VFs). OBJECTIVE: To evaluate the impact of isolated GH/IGF-I hypersecretion on bone turnover markers, Wnt inhibitors, bone mineral density (BMD), microarchitecture, bone strength and vertebral fractures in female patients with acromegaly (Acro), compared with healthy control group (HC). DESIGN, SETTING, AND PATIENTS: Cross-sectional study including 83 premenopausal women without any pituitary deficiency:18 acromegaly in remission (AcroR), 12 in group with active acromegaly (AcroA), and 53 HC. Serum procollagen type 1 N-terminal propeptide, ß-carboxy-terminal crosslinked telopeptide of type 1 collagen, osteocalcin, sclerostin, and DKK1 were measured in blood samples. dual-energy X-ray absorptiometry, high-resolution peripheral quantitative computed tomography (HR-pQCT) and vertebral fractures evaluation were also assessed simultaneously. MAIN OUTCOME AND RESULTS: AcroA showed significantly lower sclerostin and higher DKK1 compared with HC. On HR-pQCT of tibia and radius, Acro showed impairment of trabecular (area and trabecular number), increased cortical porosity, and increased cortical area and cortical thickness compared with HC. The only significant correlation found with HR-pQCT parameters was a positive correlation between cortical porosity and serum DKK1 (R = 0.45, P = 0.044). Mild VFs were present in approximately 30% of patients. CONCLUSIONS: Eugonadal women with acromegaly without any pituitary deficiency showed increased cortical BMD, impairment of trabecular bone microstructure, and increased VF. Sclerostin was not correlated with any HR-pQCT parameters; however, DKK1 was correlated with cortical porosity in tibia (P = 0.027). Additional studies are needed to clarify the role of Wnt inhibitors on bone microarchitecture impairment in acromegaly.


Asunto(s)
Acromegalia/patología , Huesos/ultraestructura , Vía de Señalización Wnt/fisiología , Adulto , Densidad Ósea , Huesos/metabolismo , Estudios Transversales , Femenino , Análisis de Elementos Finitos , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Persona de Mediana Edad , Premenopausia , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/etiología
8.
Cells ; 9(8)2020 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-32751131

RESUMEN

Wnt signaling is well-known to play major roles in the hematopoietic system, from embryogenesis to aging and disease. In addition to the main ß-catenin-dependent pathway, it is now clear that Wnt5a and the structurally related Wnt5b are essential for hematopoiesis, bone marrow colonization and the final steps of hematopoietic stem cell (HSC) maturation via ß-catenin-independent signaling. Wnt5a and Wnt5b ligands prevent hematopoietic exhaustion (by maintaining quiescent, long-term HSCs), induce the proliferation of progenitors, and guide myeloid development, in addition to being involved in the development of aging-related alterations. The aim of this review is to summarize the current knowledge on these roles of Wnt5a and Wn5b signaling in the hematopoietic field.


Asunto(s)
Hematopoyesis/fisiología , Células Madre Hematopoyéticas/metabolismo , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/fisiología , Proteína Wnt-5a/metabolismo , Animales , Diferenciación Celular/fisiología , Humanos , beta Catenina/metabolismo
9.
Artículo en Inglés | MEDLINE | ID: mdl-32328032

RESUMEN

Prostate cancer is initially dependent on the androgen, gradually evolves into an androgen-independent form of the disease, also known as castration-resistant prostate cancer (CRPC). At this stage, current therapies scantily improve survival of the patient. Androgens and estrogens are involved in normal prostate and prostate cancer development. The mechanisms by which estrogens/estrogen receptors (ERs) induce prostate cancer and promote prostate cancer progression have not yet been fully identified. Our laboratory has shown that androgen-independent prostate cancer cells PC-3 express both ERα and ERß. The activation of ERß increases the expression of ß-catenin and proliferation of PC-3 cells. We now report that the activation of ERß promotes the increase of migration, invasion and anchorage-independent growth of PC-3 cells. Furthermore, the activation of ERα also plays a role in invasion and anchorage-independent growth of PC-3 cells. These effects are blocked by pretreatment with PKF 118-310, compound that disrupts the complex ß-catenin/TCF/LEF, suggesting that ERs/ß-catenin are involved in all cellular characteristics of tumor development in vitro. Furthermore, PKF 118-310 also inhibited the upregulation of vascular endothelial growth factor A (VEGFA) induced by activation of ERs. VEGF also is involved on invasion of PC-3 cells. In conclusion, this study provides novel insights into the signatures and molecular mechanisms of ERß in androgen-independent prostate cancer cells PC-3. ERα also plays a role on invasion and colony formation of PC-3 cells.


Asunto(s)
Adenocarcinoma/patología , Movimiento Celular , Proliferación Celular , Neoplasias de la Próstata/patología , Receptores de Estrógenos/fisiología , Andrógenos/farmacología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Humanos , Masculino , Invasividad Neoplásica , Células PC-3 , Transducción de Señal/efectos de los fármacos , Ensayo de Tumor de Célula Madre , Vía de Señalización Wnt/efectos de los fármacos , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismo
10.
J Cell Physiol ; 235(11): 8293-8303, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32239701

RESUMEN

This study aimed to investigate if wingless-related integration site (Wnt) signaling participates in the high osteogenic potential of titanium with nanotopography (Ti-Nano). We showed that among the several components of the Wnt signaling pathway, Frizzled 6 (Fzd6) was the transcript most intensely modulated by nanotopography compared with the untreated Ti surface (Ti-Machined). Then, we investigated whether and how Fzd6 participates in the regulation of osteoblast differentiation caused by nanotopography. The Fzd6 silencing with CRISPR-Cas9 transfection in MC3T3-E1 cells induced a more pronounced inhibition of osteoblast differentiation of cells cultured on nanotopography than those cultured on Ti-Machined. The analysis of the expression of calcium-calmodulin-dependent protein kinase II and ß-catenin demonstrated that Fzd6 disruption inhibited the osteoblast differentiation induced by Ti-Nano by preventing the activation of Wnt/ß-catenin but not that of Wnt/Ca2+ signaling, which is usually triggered by the receptor Fzd6. These findings elucidate the biological function of Fzd6 as a receptor that triggers Wnt/ß-catenin signaling and the cellular mechanisms modulated by nanotopography during osteoblast differentiation.


Asunto(s)
Diferenciación Celular/fisiología , Receptores Frizzled/metabolismo , Osteoblastos/metabolismo , Titanio , Vía de Señalización Wnt/fisiología , Animales , Línea Celular , Nanopartículas del Metal , Ratones , Osteogénesis/fisiología , Propiedades de Superficie , Titanio/química , Titanio/farmacología
11.
Clin Transl Oncol ; 22(10): 1838-1848, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32130676

RESUMEN

PURPOSE: To investigate the role of PRDX2 in esophageal carcinoma (ESCA). METHODS: The expression of PRDX2 was detected in ESCA tissues. And PRDX2 expression in two ESCA cell lines was knocked down. Cell proliferation, metastasis and invasion were detected in these cells. RESULTS: Here, we found that PRDX2 expression was significantly increased in ESCA tissues and was associated with a poor prognosis in ESCA patients. In addition, PRDX2 expression was significantly associated with pathological grading, infiltration degree and 5-year survival time in ESCA patients. Next, we knocked down PRDX2 expression by PRDX2-shRNA transfection in two ESCA cell lines, Eca-109 and TE-1. Proliferation analysis indicated that in vitro PRDX2 knockdown decreased growth and clone formation of ESCA cells. Scratch and transwell assays indicated that cell migration and invasion were significantly inhibited by PRDX2 knockdown. In addition, PRDX2 knockdown inhibited cell cycle of ESCA cells and down-regulated Cyclin D1-CDK4/6. Moreover, PRDX2 knockdown regulated proteins involved in mitochondrial-dependent apoptosis, including increased Bax and Caspase9/3 and decreased Bcl2. Mechanism investigation indicated that PRDX2 knockdown led to inactivation of Wnt/ß-catenin and AKT pathways. CONCLUSIONS: Our data suggest that PRDX2 may function as an oncogene in the development of ESCA via regulating Wnt/ß-catenin and AKT pathways. Our study fills a gap in the understanding of the role of PRDX2 in ESCA and provides a potential target for ESCA treatment.


Asunto(s)
Neoplasias Esofágicas/etiología , Carcinoma de Células Escamosas de Esófago/etiología , Peroxirredoxinas/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Vía de Señalización Wnt/fisiología , Apoptosis , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Humanos , Peroxirredoxinas/análisis
12.
Artículo en Inglés | MEDLINE | ID: mdl-31987027

RESUMEN

Epilepsy is a neurological disorder that involves abnormal and recurrent neuronal discharges, producing epileptic seizures. Recently, it has been proposed that the Wnt signaling pathway is essential for the central nervous system development and function because it modulates important processes such as hippocampal neurogenesis, synaptic clefting, and mitochondrial regulation. Wnt/ß- catenin signaling regulates changes induced by epileptic seizures, including neuronal death. Several genetic studies associate Wnt/ß-catenin signaling with neuronal excitability and epileptic activity. Mutations and chromosomal defects underlying syndromic or inherited epileptic seizures have been identified. However, genetic factors underlying the susceptibility of an individual to develop epileptic seizures have not been fully studied yet. In this review, we describe the genes involved in neuronal excitability in epileptogenic zones dependent on the Wnt/ß-catenin pathway.


Asunto(s)
Epilepsia/metabolismo , Neuronas/metabolismo , Vía de Señalización Wnt/fisiología , Hipocampo , Humanos , Fenómenos Fisiológicos del Sistema Nervioso , Neurogénesis , Convulsiones/metabolismo , beta Catenina/metabolismo
13.
Mol Neurobiol ; 57(3): 1389-1404, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31745835

RESUMEN

Wnt ligands play critical roles in neuronal development, synapse formation, synaptic activity, and plasticity. Synaptic plasticity requires molecular remodeling of synapses, implying the expression of key synaptic components. Some studies have linked Wnt signaling activity to changes in synaptic protein levels. However, the presynaptic and postsynaptic gene expression profiles of hippocampal neurons exposed to Wnt proteins have not been studied. Hence, we treated rat cultured hippocampal neurons with recombinant Wnt3a, lithium, and the Wnt inhibitor Dkk-1 for different treatment durations and measured the mRNA and protein levels of pre- and postsynaptic components. The ligand Wnt3a promoted the differential temporal expression of genes encoding presynaptic and postsynaptic proteins. Gene expression of the presynaptic proteins Rim1, piccolo (Pclo), Erc2, Ctbp1 and Rimbp2 increased in a specific temporal pattern. Simultaneously, the mRNA and protein levels of postsynaptic components showed a different temporal expression pattern, e.g., the mRNAs for postsynaptic scaffolding components such as postsynaptic density protein-95 (PSD-95/Dlg4), Homer1 and Shank1 were temporally regulated by both Wnt3a and lithium. On the other hand, the mRNA levels of the gene encoding the protein calcium/calmodulin-dependent protein kinase IV (Camk4), canonically upregulated by Wnt, were increased. Our results suggest that Wnt signaling orchestrates expressional changes in genes encoding presynaptic and postsynaptic components, probably as part of a synaptic plasticity mechanism in neurons.


Asunto(s)
Plasticidad Neuronal/fisiología , Sinapsis/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Hipocampo/metabolismo , Ratones , Neurogénesis/fisiología , Terminales Presinápticos/metabolismo , Ratas , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/genética
14.
Aging (Albany NY) ; 11(16): 5924-5942, 2019 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-31447429

RESUMEN

Age represents the highest risk factor for death due to cardiovascular disease. Heart failure (HF) is the most common cardiovascular disease in elder population and it is associated with cognitive impairment (CI), diminishing learning and memory process affecting life quality and mortality in these patients. In HF, CI has been associated with inadequate O2 supply to the brain; however, an important subset of HF patients displays CI with almost no alteration in cerebral blood flow. Importantly, nothing is known about the pathophysiological mechanisms underpinning CI in HF with no change in brain tissue perfusion. Here, we aimed to study memory performance and learning function in a rodent model of HF that shows no change in blood flow going to the brain. We found that HF rats presented learning impairments and memory loss. In addition, HF rats displayed a decreased level of Wnt/ß-catenin signaling downstream elements in the hippocampus, one pathway implicated largely in aging diseases. Taken together, our results suggest that in HF rats CI is associated with dysfunction of the Wnt/ß-catenin signaling pathway. The mechanisms involved in the alterations of Wnt/ß-catenin signaling in HF and its contribution to the development/maintenance of CI deserves future investigations.


Asunto(s)
Disfunción Cognitiva/metabolismo , Insuficiencia Cardíaca/metabolismo , Hipocampo/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/complicaciones , Aprendizaje por Laberinto/fisiología , Ratas , Memoria Espacial/fisiología , beta Catenina/metabolismo
15.
Acta Cir Bras ; 34(5): e201900502, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31166463

RESUMEN

PURPOSE: To investigate inhibitory effect of Astragalus polysaccharide (APS) on osteoporosis in ovariectomized rats by regulating FoxO3a/Wnt2 signaling pathway. METHODS: Postmenopausal osteoporosis (PMOP) animal model was developed by excising the bilateral ovaries of rats. The model rats were administered with APS (200 mg/kg, 400 mg/kg, 800 mg/kg) by intragastric administration once daily for 12 weeks. Bone density, bone metabolism index and oxidative stress index were measured in all groups. Furthermore, the regulation of APS of FoxO3a / Wnt2 signaling pathway was observed. RESULTS: APS has an estrogen-like effect, which can increase bone mass, lower serum ALP and BGP values, increase blood calcium content, and increase bone density of the femur and vertebrae in rats. At the same time, APS can increase the bone mineral content of the femur, increase the maximum stress, maximum load and elastic modulus of the ovariectomized rats, improve oxidative stress in rats by increasing the gene expression of ß-catenin and Wnt2 mRNA and inhibiting the gene expression of FoxO3a mRNA. CONCLUSION: Astragalus polysaccharide can effectively alleviate oxidative stress-mediated osteoporosis in ovariectomized rats, which may be related to its regulation of FoxO3a/Wnt2/ß-catenin pathway.


Asunto(s)
Planta del Astrágalo/química , Proteína Forkhead Box O3/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Polisacáridos/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Densidad Ósea/efectos de los fármacos , Femenino , Fémur/efectos de los fármacos , Fémur/metabolismo , Proteína Forkhead Box O3/análisis , Expresión Génica/efectos de los fármacos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/análisis , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/efectos de los fármacos , Osteoporosis/metabolismo , Ovariectomía , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Distribución Aleatoria , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Valores de Referencia , Reproducibilidad de los Resultados , Resultado del Tratamiento , Vía de Señalización Wnt/fisiología , Proteína wnt2/análisis , Proteína wnt2/efectos de los fármacos , beta Catenina/análisis , beta Catenina/efectos de los fármacos
16.
J Cell Physiol ; 234(12): 22130-22143, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31087357

RESUMEN

In the last 40 years ovarian cancer mortality rates have slightly declined and, consequently, it continues to be the fifth cause of cancer death in women. In the present study, we showed that ß-catenin signaling is involved in the functions of ovarian cancer cells and interacts with the Notch system. Wnt and Notch systems showed to be prosurvival for ovarian cancer cells and their inhibition impaired cell proliferation and migration. We also demonstrated that the inhibition of ß-catenin by means of two molecules, XAV939 and ICG-001, decreased the proliferation of the IGROV1 and SKOV3 ovarian cancer cell lines and that ICG-001 increased the percentage of IGROV1 cells undergoing apoptosis. The simultaneous inhibition of ß-catenin and Notch signaling, by using the DAPT inhibitor, decreased ovarian cancer cell proliferation to the same extent as targeting only the Wnt/ß-catenin pathway. A similar effect was observed in IGROV1 cell migration with ICG-001 and DAPT. ICG-001 increased the Notch target genes Hes-1 and Hey-1 and increased Jagged1 expression. However, no changes were observed in Dll4 or Notch 1 and 4 expressions. Our results suggest that Notch and ß-catenin signaling co-operate in ovarian cancer to ensure the proliferation and migration of cells and that this could be achieved, at least partly, by the upregulation of Notch Jagged1 ligand in the absence of Wnt signaling. We showed that the Wnt pathway crosstalks with Notch in ovarian cancer cell functions, which may have implications in ovarian cancer therapeutics.


Asunto(s)
Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/patología , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Vía de Señalización Wnt/fisiología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Carcinoma Epitelial de Ovario/metabolismo , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Supervivencia Celular , Diaminas/farmacología , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/metabolismo , Pirimidinonas/farmacología , Tiazoles/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
17.
ScientificWorldJournal ; 2019: 4714781, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30940992

RESUMEN

For gastrulation to occur in human embryos, a mechanism that simultaneously regulates many different processes, such as cell differentiation, proliferation, migration, and invasion, is required to consistently and effectively create a human being during embryonic morphogenesis. The striking similarities in the processes of cancer and gastrulation have prompted speculation regarding the developmental pathways involved in their regulation. One of the fundamental requirements for the developmental pathways in gastrulation and cancer is the ability to respond to environmental stimuli, and it has been proposed that the Kaiso and noncanonical Wnt pathways participate in the mechanisms regulating these developmental pathways. In particular, these pathways might also explain the notable differences in invasive capacity between cancers of endodermal and mesodermal origins and cancers of ectodermal origin. Nevertheless, the available information indicates that cancer is an abnormal state of adult human cells in which developmental pathways are reactivated in inappropriate temporal and spatial contexts.


Asunto(s)
Modelos Biológicos , Neoplasias/metabolismo , Vía de Señalización Wnt/fisiología , Diferenciación Celular , Movimiento Celular , Epigénesis Genética , Gastrulación , Regulación del Desarrollo de la Expresión Génica , Humanos , Neoplasias/genética , Proteínas Wnt/metabolismo
18.
An Acad Bras Cienc ; 91(1): e20180459, 2019 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-30916158

RESUMEN

This study aimed to investigate how 6-bromoindirubin-3'-oxime (BIO) increases the osteogenic differentiation of canine bone mesenchymal stem cells (BMSCs) and the role of the Wnt/ß-catenin signaling pathway in this process. We mimicked the effect of Wnt by adding BIO to the culture medium of BMSCs and examined whether canonical Wnt signaling positively affects the differentiation of these cells into osteoblasts. Canine BMSCs were cultured with 0.5 and 1.0 µM BIO under osteogenic conditions and then differentiation markers were investigated. It was found that BIO significantly increased the activity of alkaline phosphatase (ALP), the number of ALP-positive cells, the mineralization level and calcium deposits. Moreover, cells cultured with 0.5 and 1.0 µM BIO exhibited detectable ß-catenin expression in their nuclei, and showed upregulated ß-catenin and glycogen synthase kinase 3 beta(GSK3ß) phosphorylation compared to untreated cells. In addition, BIO enhanced the mRNA expression of osteoblast differentiation markers such as ALP, runt-related transcription factor 2, collagen I, osteocalcin, and osteonectin. In conclusion, BIO upregulated GSK3ß phosphorylation and inhibited its activity, thereby activating the Wnt/ß-catenin signaling pathway and promoting the osteogenic differentiation of canine BMSCs. The effect of 1.0 µM BIO on BMSCs differentiation was stronger than that of 0.5 µM BIO.


Asunto(s)
Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Indoles/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Oximas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Animales , Enfermedades de los Perros/tratamiento farmacológico , Enfermedades de los Perros/metabolismo , Perros , Indoles/uso terapéutico , Células Madre Mesenquimatosas/citología , Osteoblastos/citología , Osteogénesis/genética , Osteogénesis/fisiología , Oximas/uso terapéutico , Transducción de Señal , Proteínas Wnt/metabolismo , Vía de Señalización Wnt/fisiología
19.
J Neurochem ; 149(1): 54-72, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30300917

RESUMEN

Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). In mouse models of AD, activation of the canonical Wnt signaling pathway improves learning/memory, but the mechanism for this remains unclear. The decline in brain function in AD patients correlates with reduced glucose utilization by neurons. Here, we test whether improvements in glucose metabolism mediate the neuroprotective effects of Wnt in AD mouse model. APPswe/PS1dE9 transgenic mice were used to model AD, Andrographolide or Lithium was used to activate Wnt signaling, and cytochalasin B was used to block glucose uptake. Cognitive function was assessed by novel object recognition and memory flexibility tests. Glucose uptake and the glycolytic rate were determined using radiotracer glucose. The activities of key enzymes of glycolysis such as hexokinase and phosphofructokinase, Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) levels and the pentose phosphate pathway and activity of glucose-6 phosphate dehydrogenase were measured. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. Wnt signaling enhanced glucose metabolism by increasing the expression and/or activity of hexokinase, phosphofructokinase and AMP-activated protein kinase. Inhibiting glucose uptake partially abolished the beneficial effects of Wnt signaling on learning/memory. Wnt activation also enhanced glucose metabolism in cortical and hippocampal neurons, as well as brain slices derived from APPswe/PS1E9 transgenic mice. Combined, these data provide evidence that the neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt-mediated improvements in neuronal glucose metabolism.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Glucosa/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Humanos , Ratones , Ratones Transgénicos , Ratas
20.
Mol Neurobiol ; 56(2): 1517-1530, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29948952

RESUMEN

Glioblastoma is an extremely aggressive and deadly brain tumor known for its striking cellular heterogeneity and capability to communicate with microenvironment components, such as microglia. Microglia-glioblastoma interaction contributes to an increase in tumor invasiveness, and Wnt signaling pathway is one of the main cascades related to tumor progression through changes in cell migration and invasion. However, very little is known about the role of canonical Wnt signaling during microglia-glioblastoma crosstalk. Here, we show for the first time that Wnt3a is one of the factors that regulate interactions between microglia and glioblastoma cells. Wnt3a activates the Wnt/ß-catenin signaling of both glioblastoma and microglial cells. Glioblastoma-conditioned medium not only induces nuclear translocation of microglial ß-catenin but also increases microglia viability and proliferation as well as Wnt3a, cyclin-D1, and c-myc expression. Moreover, glioblastoma-derived Wnt3a increases microglial ARG-1 and STI1 expression, followed by an upregulation of IL-10 mRNA levels, and a decrease in IL1ß gene expression. The presence of Wnt3a in microglia-glioblastoma co-cultures increases the formation of membrane nanotubes accompanied by changes in migration capability. In vivo, tumors formed from Wnt3a-stimulated glioblastoma cells presented greater microglial infiltration and more aggressive characteristics such as growth rate than untreated tumors. Thus, we propose that Wnt3a belongs to the arsenal of factors capable of stimulating the induction of M2-like phenotype on microglial cells, which contributes to the poor prognostic of glioblastoma, reinforcing that Wnt/ß-catenin pathway can be a potential therapeutic target to attenuate glioblastoma progression.


Asunto(s)
Microglía/metabolismo , Vía de Señalización Wnt/fisiología , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Glioblastoma/genética , Humanos , Fenotipo
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