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1.
Chem Biol Interact ; 320: 109022, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32112862

RESUMEN

Epithelial mesenchymal transformation plays a crucial role in the metastasis of bladder cancer, which makes bladder cancer difficult to cure. Bladder cancer is the most common malignancy of the urinary system, and distant metastasis is the leading cause of death. Therefore, finding a bioactive drug that can specifically inhibit epithelial mesenchymal transformation may be a new direction for bladder cancer treatment in the future. Thymoquinone (TQ), the major active compound isolated from black seed oil (Nigella sativa), has been reported to exhibit anti-inflammatory and anticancer abilities. TQ can exhibit its antitumor effect by inhibiting the proliferation and metastasis of cancer cells. However, the underlying mechanism of TQ as a tumor inhibitor in bladder cancer remains poorly understood. First, in this research, we demonstrate that TQ can reverse EMT by upregulating epithelial markers, such as E-cadherin, and downregulating mesenchymal markers, such as N-cadherin and vimentin. Furthermore, we demonstrate that TQ can suppress the activation of the Wnt/ß-catenin signaling pathway and inhibit the expression of ß-catenin target genes, such as MYC, Axin-2, MMP7, CyclinD1 and MET, which play crucial roles in EMT and cancer progression. Additionally, we demonstrate that TQ can inhibit the growth of xenografts and restrict the formation of tumor metastatic foci in the lung. Taken together, our findings confirm the antimetastatic effect of TQ in bladder cancer cells for the first time and also provide new evidence for the development of TQ as a novel treatment for metastatic bladder cancer.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Benzoquinonas/farmacología , Supervivencia Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Benzoquinonas/química , Línea Celular Tumoral , Ensayos de Migración Celular , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estructura Molecular , Proteínas Wnt/genética , beta Catenina/genética
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 275-282, 2020 Feb.
Artículo en Chino | MEDLINE | ID: mdl-32027289

RESUMEN

OBJECTIVE: To investigate the effect of prostaglandin E2 recoptor 4 antagonist (EP4A) on the self-renewal ability of human CD34+ cells and its mechamism. METHODS: The peripheral blood hematopoietic stem cell of 20 healthy donors received the G-CSF-mobilization were collected, then the human CD34+ cells were sorted out by MACS microbead kit. The human CD34+ cells were treated with DMSO (control group), EP4A (EP4A group) and EP4A+EP4A antagonist (EP4A+EP4A group) for 72 hours. The differential genes and pathways related with CD34+ cell stemness were detected by Thermogram and Pathway enrichment analysis. and then the expression levels of protein and gene (ß-catenin, Nanog, Oct4, Sox2, Stat3, AKT, P38) were detected by qRT-PCR and Western blot respectively. RESULTS: EP4A could elevate the mRNA and protein expression of ß-catenin, Nanog, Oct4, Sox2, in comparison with control group, however, mRNA and protein expression of STAT3, AKT, P38 were not changed. When human CD34+ cell were cultured with EP4A+XAV939 it was found that the mRNA and protein expression of ß-catenin was downregulated, moreover the mRNA and protein expression of Nanog, Oct4, Sox2 were reduced. CONCLUSION: EP4A can upregulate stemness factors-ß-catenin, Nanog, Oct4 and Sox2 in human CD34+ cell in vitro, but not STAT3, AKT and P38.


Asunto(s)
Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Antígenos CD34 , Movimiento Celular , Factor Estimulante de Colonias de Granulocitos , Humanos , Proteína Homeótica Nanog , Factor 3 de Transcripción de Unión a Octámeros , Prostaglandinas , ARN Mensajero , Linfocitos T
3.
Gen Physiol Biophys ; 39(1): 59-67, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32039825

RESUMEN

MT1JP is a LncRNA that is reportedly involved in gastric cancer development, but a biological role and mechanism for MT1JP in breast cancer is unknown. Quantitative RT-PCR was performed to detect the level of MT1JP and miR-92a-3p, and Western blotting assays ware performed to measure the expression of CDK2, cyclinE1, P21, CD151, CD147, MMP2 and MMP9 in breast cells. Subsequently, cell viability was analyzed with CCK-8 assay. Cell migration and invasion were analyzed with Transwell and Scratch Test, respectively. The results demonstrated that MT1JP was significantly down-regulated in breast cells. Additionally, we found that overexpression of MT1JP in breast cancer cells significantly inhibited cell proliferation, migration and invasion, and regulate the expression of CDK2, cyclinE1 and P21. We then investigated a possible mechanism for these results, MT1JP significantly inhibited CD151, CD147, MMP2 and MMP9 protein expression in breast cancer cells. Moreover, we found that MT1JP binds to and negatively regulates miR-92-3p, which is known to be an oncogene in some human cancers. Our data indicate that MT1JP functions as an anti-tumor LncRNA and downregulates miR-92-3p, CD151 and CD147, and may serve as a novel diagnostic and therapeutic marker in breast cancer.


Asunto(s)
Neoplasias de la Mama , MicroARNs/genética , ARN Largo no Codificante/genética , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos
4.
J Photochem Photobiol B ; 204: 111806, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32044619

RESUMEN

The cotton fabrics are a cosmopolitan in usage due to their extraordinary features. The clothes are a very good medium for the growth of pathogenic microorganisms. The nanoparticles have diverse benefits in the biomedical field like drug carrier and as antimicrobials. The current investigation was aimed to synthesize the metallic silver nanoparticles (AgNPs) from the aqueous extract of Curcuma longa leaf and evaluating their antimicrobial and wound healing potential of AgNPs coated cotton fabric. The synthesized AgNPs were characterized by HR-TEM and FT-IR examinations. The formulated AgNPs were coated with cotton fabrics to test their efficiency against the pathogenic microorganisms. The existence of AgNPs in the cotton fabrics was confirmed via the SEM along with EDX analysis. The antimicrobial potential of fabricated AgNPs and its coated cotton fabrics was inspected against the human pathogenic strains. The wound healing efficacy was examined in the L929 cells. The HR-TEM analysis proved the existence of spherical shaped AgNPs. In the antimicrobial activity, the CL-AgNPs loaded cotton fabric was exhibited an appreciable decrease in the growth of pathogenic microorganisms. The crude extract, as well as formulated AgNPs, also exhibited the noticeable antimicrobial potency against the S.aureus, P.aeruginosa, S.pyogenes, and C.albicans. The AgNPs loaded cotton fabrics was displayed the potent wound healing activity in the fibroblast (L929) cells. Consequently, it was concluded that the formulated AgNPs from C.longa coated cotton fabrics may be utilized for the variety of applications in hospital patients and even medical workers to prevent the microbial infection.


Asunto(s)
Antiinfecciosos/química , Fibra de Algodón/análisis , Curcuma/química , Nanopartículas del Metal/química , Plata/química , Animales , Antiinfecciosos/farmacología , Candida albicans/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Curcuma/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Tecnología Química Verde , Nanopartículas del Metal/toxicidad , Ratones , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/química , Hojas de la Planta/química , Hojas de la Planta/metabolismo
5.
BMC Med Genet ; 21(1): 26, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32028920

RESUMEN

BACKGROUND: While Miller-Dieker syndrome critical region deletions are well known delineated anomalies, submicroscopic duplications in this region have recently emerged as a new distinctive syndrome. So far, only few cases have been described overlapping 17p13.3 duplications. METHODS: In this study, we report on clinical and cytogenetic characterization of two new cases involving 17p13.3 and 3p26 chromosomal regions in two sisters with familial history of lissencephaly. Fluorescent In Situ Hybridization and array Comparative Genomic Hybridization were performed. RESULTS: A deletion including the critical region of the Miller-Dieker syndrome of at least 2,9 Mb and a duplication of at least 3,6 Mb on the short arm of chromosome 3 were highlighted in one case. The opposite rearrangements, 17p13.3 duplication and 3p deletion, were observed in the second case. This double chromosomal aberration is the result of an adjacent 1:1 meiotic segregation of a maternal reciprocal translocation t(3,17)(p26.2;p13.3). CONCLUSIONS: 17p13.3 and 3p26 deletions have a clear range of phenotypic features while duplications still have an uncertain clinical significance. However, we could suggest that regardless of the type of the rearrangement, the gene dosage and interactions of CNTN4, CNTN6 and CHL1 in the 3p26 and PAFAH1B1, YWHAE in 17p13.3 could result in different clinical spectrums.


Asunto(s)
Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/genética , Lisencefalia/genética , Neuronas/patología , Translocación Genética/genética , 1-Alquil-2-acetilglicerofosfocolina Esterasa/genética , Proteínas 14-3-3/genética , Moléculas de Adhesión Celular/genética , Movimiento Celular/genética , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 3/genética , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/diagnóstico , Lisencefalias Clásicas y Heterotopias Subcorticales en Banda/fisiopatología , Hibridación Genómica Comparativa , Contactinas/genética , Femenino , Dosificación de Gen/genética , Estudios de Asociación Genética , Humanos , Hibridación Fluorescente in Situ , Lisencefalia/diagnóstico , Lisencefalia/fisiopatología , Meiosis/genética , Proteínas Asociadas a Microtúbulos/genética , Neuronas/metabolismo , Fenotipo , Trisomía/genética
6.
Medicine (Baltimore) ; 99(8): e19171, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32080097

RESUMEN

Circular RNAs (circRNAs), a widespread type of noncoding RNA, are produced by reverse splicing with a circular loop structure. Circ_VCAN (hsa_circ_0073237) acts as a novel circRNA, although its roles in the progression and radioresistance of glioma remain unknown.Expressions of circ_VCAN and microRNA-1183 (miR-1183) were analyzed by quantitative real-time PCR, and the functions of circ_VCAN and irradiate in glioma cell proliferation, apoptosis, migration, and invasion were assessed using cell counting kit-8, flow cytometry, Wound healing, and Transwell assays. The interaction between circ_VCAN and miR-1183 was validated dual-luciferase reporter assay.Our results revealed that circ_VCAN was significantly upregulated in radioresistant glioma tissues compared with radiosensitive tissues, and that circ_VCAN expression was negatively correlated with miR-1183 expression in glioma tissues. We also determined that circ_VCAN expression was decreased and miR-1183 expression was increased in U87 and U251 cells after irradiation. Both knockdown of circ_VCAN and treatment with miR-1183 mimics inhibited proliferation, migration, and invasion, and accelerated apoptosis of the irradiated U87 and U251 cells. In addition, luciferase reporter assays revealed that circ_VCAN might function as a sponge for miR-1183. Finally, overexpression of circ_VCAN expedited carcinogenesis and reduced glioma radiosensitivity by regulating miR-1183.Circ_VCAN serves as a potential oncogene of glioma by regulating miR-1183, and plays an essential role in the radioresistance of glioma.


Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , MicroARNs/genética , Versicanos/genética , Apoptosis , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Carcinogénesis/genética , Carcinogénesis/efectos de la radiación , Movimiento Celular , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Glioma/patología , Glioma/radioterapia , Humanos , Regulación hacia Arriba/genética , Regulación hacia Arriba/efectos de la radiación
7.
Planta Med ; 86(5): 348-355, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32045946

RESUMEN

Digitaria ciliaris is widely reported to be a problematic weed in agricultural areas and is mainly used as an indicator plant for the development of herbicides. However, its bioactivities on skin regeneration and wound healing have not been investigated. In the present study, we investigated the effects of D. ciliaris flower absolute on skin wound healing and skin regeneration-related events, that is, proliferation, migration, and collagen biosynthesis, in human fibroblasts and keratinocytes. For this study, we extracted absolute from the D. ciliaris flower by solvent extraction and identified the composition of D. ciliaris flower absolute using GC/MS analysis. We also tested the effect of D. ciliaris flower absolute in CCD986sk fibroblasts and/or HaCaT keratinocytes using the WST assay and 5-bromo-2'-deoxyuridine incorporation assay, Boyden chamber assay, ELISA, sprouting assay, and immunoblotting. GC/MS analysis of D. ciliaris flower absolute revealed that it contained 15 compounds. The absolute increased the proliferations of keratinocytes and fibroblasts and the migration of fibroblasts but did not affect cell viabilities. In addition, it enhanced the syntheses of type I and IV collagen in fibroblasts, but not in keratinocytes. The sprouting assay showed increased sprout outgrowth of fibroblasts. In addition, D. ciliaris flower absolute induced the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in fibroblasts. These results indicate that D. ciliaris flower absolute may promote skin wound healing/regeneration by inducing the proliferation, migration, and collagen synthesis of fibroblasts, as well as the proliferation of keratinocytes. Therefore, D. ciliaris flower absolute may be a potential natural source for cosmetic or pharmaceutical agents that promote skin wound healing/regeneration.


Asunto(s)
Digitaria , Queratinocitos , Movimiento Celular , Proliferación Celular , Fibroblastos , Flores , Humanos , Extractos Vegetales , Piel , Cicatrización de Heridas
8.
Life Sci ; 248: 117445, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32081664

RESUMEN

AIMS: Atherosclerosis (AS) is a common cardiovascular disease with complicated pathogenesis. Long non-coding RNAs (lncRNAs) have been reported to be associated with AS progression. We aimed to explore the role and underlying mechanism of HOXA transcript at the distal tip (HOTTIP) in AS. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of HOTTIP, miR-490-3p and high mobility group B 1 (HMGB1) in AS patients' sera and oxidized low-density lipoprotein (ox-LDL) induced human aortic vascular smooth muscle cells (HA-VSMCs). Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to evaluate the proliferation and migration of HA-VSMCs, respectively. Western blot assay was carried out to determine the levels of proliferating cell nuclear antigen (PCNA), matrix metalloprotein 2 (MMP2), MMP9 and HMGB1. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the targeting association between HOTTIP and miR-490-3p, as well as miR-490-3p and HMGB1. KEY FINDINGS: HOTTIP and HMGB1 were upregulated and miR-490-3p was downregulated in the sera of AS patients and ox-LDL-stimulated HA-VSMCs. HOTTIP knockdown suppressed ox-LDL induced proliferation and migration in HA-VSMCs. MiR-490-3p was identified as a target of HOTTIP and HOTTIP overexpression abolished the inhibition on cell proliferation and migration mediated by miR-490-3p in ox-LDL-induced HA-VSMCs. Moreover, miR-490-3p inhibition promoted cell proliferation and migration by directly targeting HMGB1 in ox-LDL-induced HA-VSMCs. Besides, HOTTIP knockdown repressed the activation of PI3K-AKT signaling pathway. SIGNIFICANCE: HOTTIP knockdown suppressed cell proliferation and migration by regulating miR-490-3p/HMGB1 axis and PI3K-AKT pathway in ox-LDL-induced HA-VSMCs.


Asunto(s)
Aterosclerosis/genética , Proteína HMGB1/genética , MicroARNs/genética , Miocitos del Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Largo no Codificante/genética , Aorta/metabolismo , Aorta/patología , Aterosclerosis/sangre , Aterosclerosis/patología , Estudios de Casos y Controles , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Regulación de la Expresión Génica , Proteína HMGB1/metabolismo , Humanos , Lipoproteínas LDL/farmacología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , MicroARNs/metabolismo , Persona de Mediana Edad , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/antagonistas & inhibidores , ARN Largo no Codificante/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal
9.
Life Sci ; 248: 117454, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32088211

RESUMEN

AIMS: Dihydroartemisinin (DHA) is currently considered as the promising cancer therapeutic drug. In this study, we aimed to investigate the anti-proliferative and anti-metastasis effects of DHA. MAIN METHODS: Utilizing breast cancer cells MCF-7, MDA-MB-231 and BT549, cell proliferation, migration and invasion were detected. RT-qPCR was performed to detect CIZ1, TGF-ß1 and Snail expression, and the interactions of these related molecules were analyzed by GeneMANIA database. Western blot detected CIZ1, TGF-ß1/Smads signaling and Snail expression in DHA-treated cells, in TGFß1-induced cells with enhanced metastatic capacity, and in cells treated with DHA plus TGFß1/TGFß1 inhibitor SD-208. KEY FINDINGS: Results indicated DHA inhibited breast cancer cell proliferation and migration, with more potent effects compared with that of artemisinin. RT-qPCR and Western blot showed DHA inhibited CIZ1, TGF-ß1 and Snail expression, and these molecules were shown to have protein-protein interactions by bioinformatics. Furthermore, TGFß1-treatment enhanced MCF-7 migration and invasion, and CIZ1, TGF-ß1/Smads signaling and snail activities; DHA, SD-208, combination of DHA and SD-208 reversed these conditions, preliminarily proving the cascade regulation between TGF-ß1 signaling and CIZ1. MCF-7 xenografts model demonstrated the inhibition of DHA on tumor burden, and its mechanisms and well-tolerance in vivo; combination of DHA and SD-208 tried by us for the first time showed better treatment effects, but possible liver impairment made its use still keep cautious. SIGNIFICANCE: DHA treatment inhibits the proliferation and metastasis of breast cancer, through suppressing TGF-ß1/Smad signaling and CIZ1, suggesting the promising potential of DHA as a well-tolerated antitumor TGF-ß1 pathway inhibitor.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Artemisininas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Proteínas Nucleares/genética , Factor de Crecimiento Transformador beta1/genética , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal , Femenino , Humanos , Metástasis Linfática , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Pteridinas/farmacología , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factores de Transcripción de la Familia Snail/antagonistas & inhibidores , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Life Sci ; 248: 117449, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32088212

RESUMEN

AIMS: Prostate cancer (PCa) is the most common type of cancer and a major cause of death in men worldwide. Aberrant Androgen receptor (AR) and PI3K-AKT signaling are very frequent in PCa patients and, therefore, considered as therapeutic targets in the clinic. Sin1 is an essential component of mTORC2 complex, which determines full AKT activation and PCa development in PTEN-/- mice. Here we examined the role of Sin1 in human PCa cell lines and respective tumor samples. MAIN METHODS: Western blotting and immunohistochemistry (IHC) were performed to analyze the expression of Sin1-mTORC2-AKT related proteins in human PCa cells, as well as prostate tumors and normal tissue counterparts. Cell viability and invasion assays were also pursued in the presence or not of Sin1 in PCa cells. Immunoprecipitation assays were additionally carried out to examine the interaction of Sin1 with AR. KEY FINDINGS: We have presently demonstrated that high levels of Sin1 expression in human PCa tissues correlate with cancer progression. Sin1-mediated cell proliferation and invasion of PCa cells occurs by regulating mTORC2-AKT signaling, epithelial-mesenchymal transition and matrix metalloproteinases. Moreover, androgens are able to induce Sin1 expression, which is further translocated to the nucleus of PCa cells. Finally, Sin1 interacts with AR to suppress its transcriptional activity. SIGNIFICANCE: Taken together, these data indicate that both Sin1-mediated mTORC2-AKT signaling and Sin1-AR interaction regulate PCa development. Hence, Sin1 may be considered a novel biomarker of PCa progression.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Regulación Neoplásica de la Expresión Génica , Diana Mecanicista del Complejo 2 de la Rapamicina/genética , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-akt/genética , Receptores Androgénicos/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/genética , Humanos , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Análisis de Matrices Tisulares
11.
Life Sci ; 248: 117465, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32105707

RESUMEN

BACKGROUND: Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS: In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS: FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION: These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.


Asunto(s)
Factor 6 de Crecimiento de Fibroblastos/genética , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/genética , Músculo Esquelético/metabolismo , Traumatismos de los Nervios Periféricos/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Regeneración/genética , Animales , Diferenciación Celular , Línea Celular , Movimiento Celular , Proliferación Celular , Ciclina D1/genética , Ciclina D1/metabolismo , Factor 6 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Factor 6 de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Desnervación Muscular/métodos , Músculo Esquelético/inervación , Músculo Esquelético/patología , Proteína MioD/genética , Proteína MioD/metabolismo , Mioblastos/metabolismo , Mioblastos/patología , Miogenina/genética , Miogenina/metabolismo , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/patología , Cultivo Primario de Células , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Nervio Ciático/lesiones
12.
Life Sci ; 248: 117469, 2020 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-32109485

RESUMEN

AIMS: Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms. MAIN METHODS: MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. KEY FINDINGS: Our results demonstrated that SB939 at 0.5-1 µmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. SIGNIFICANCE: Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Femenino , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Vimentina/genética , Vimentina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Ann Hematol ; 99(3): 431-441, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32006153

RESUMEN

Macrophages are characterized by phenotypical and functional heterogeneity. In different microenvironments, macrophages can polarize into two types: classically activated macrophages (M1) or alternatively activated macrophages (M2). M1 macrophages are a well-known bacteriostatic macrophage, and conversely, M2 macrophages may play an important role in tumor growth and tissue remodeling. M1 macrophages have been reported to have high intracellular iron stores, while M2 macrophages contain lower intracellular iron. It has been well-described that disturbances of iron homeostasis are associated with altered immune function. Thus, it is important to investigate if chronic iron overload is capable of polarizing macrophages. Human monocytic leukemia THP-1 cells were maintained in culture medium that contained 100 µM ferrous sulfate heptahydrate (FeSO4) (I-THP-1) and differentiated into THP-1-derived macrophages (I-TDMs) by induction with phorbol 12-myristate 13-acetate (PMA). We characterized that I-TDMs not only enhanced the surface expression of CD163 and CD206 but also increased arginase and decreased iNOS protein expression. I-TDMs enhanced pSTAT6 expression and decreased pSTAT1 and NF-κB expressions. Furthermore, the gene expression profile of I-TDMs was comparable with M2 macrophages by performing human oligonucleotide DNA microarray analysis. Finally, functional assays demonstrated I-TDMs secreted higher levels of IL-10 but not M1 cytokines. Additionally, the conditional medium of I-TDMs had enhanced migration and increased invasion of A375 melanoma cells which was similar to the characteristics of tumor-associated macrophages. Taken together, we demonstrated that THP-1-derived macrophages polarized to a phenotype of M2-like characteristics when subjected to chronic iron overload.


Asunto(s)
Movimiento Celular/inmunología , Sobrecarga de Hierro/inmunología , Macrófagos/inmunología , Monocitos/inmunología , Movimiento Celular/efectos de los fármacos , Compuestos Ferrosos/efectos adversos , Compuestos Ferrosos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Sobrecarga de Hierro/inducido químicamente , Sobrecarga de Hierro/patología , Macrófagos/patología , Monocitos/patología , Células THP-1 , Acetato de Tetradecanoilforbol/farmacología
14.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 37(1): 105-111, 2020 Feb 25.
Artículo en Chino | MEDLINE | ID: mdl-32096383

RESUMEN

The article aims to explore the optimal concentration of arsenic trioxide (As 2O 3) on HepG2 of liver cancer cells, and the effect of As 2O 3 on the migration, invasion and apoptosis of HepG2 cells. In this study, the activity of HepG2 cells treated with 0, 1, 2, 4, 8, 16, 32 µmol/L As 2O 3 was tested by CCK-8 method, the semi-inhibitory concentration (IC50) was calculated, and the morphological changes of HepG2 cells were observed after the action of As 2O 3 at IC50 concentration for 12, 24, 48 h. The effect of As 2O 3 on cell migration and invasion ability was verified by wound healing experiment and Transwell invasion experiment. Western blot and qRT-PCR were used to detect the effects of As 2O 3 on the gene and protein expression levels related to cell migration, invasion and apoptosis. The results showed that, compared with the control group, the activity of HepG2 cells decreased with the increase of the concentration of As 2O 3 treatment, showing a dose-dependent effect, and its IC50 was 7.3 µmol/L. After 24 hours' treatment with 8 µmol/L As 2O 3, HepG2 cells underwent significant apoptosis, and its migration and invasion abilities were significantly reduced. In addition, the protein expression levels of RhoA, Cdc42, Rac1 and matrix metalloproteinase-9 (MMP-9) were down-regulated, the protein and mRNA expression levels of anti-apoptotic gene Bcl-2 were significantly down-regulated, and the protein and mRNA expression levels of pro-apoptotic genes Bax and Caspase-3 were significantly up-regulated. The above results indicate that certain concentration of As 2O 3 can inhibit the migration and invasion of hepatocellular carcinoma cells and promote the apoptosis of hepatocellular carcinoma cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Trióxido de Arsénico/farmacología , Carcinoma Hepatocelular/patología , Movimiento Celular/efectos de los fármacos , Neoplasias Hepáticas/patología , Proliferación Celular , Células Hep G2 , Humanos , Invasividad Neoplásica
15.
Nature ; 579(7798): 284-290, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32103175

RESUMEN

Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.


Asunto(s)
Epigénesis Genética , Terapia Genética , Células Supresoras de Origen Mieloide/fisiología , Neoplasias/terapia , Microambiente Tumoral , Animales , Azacitidina/farmacología , Benzamidas/farmacología , Diferenciación Celular , Movimiento Celular/efectos de los fármacos , Quimioterapia Adyuvante , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Ratones , Células Supresoras de Origen Mieloide/citología , Metástasis de la Neoplasia/terapia , Neoplasias/cirugía , Piridinas/farmacología , Receptores CCR2/genética , Receptores de Interleucina-8B/genética , Microambiente Tumoral/efectos de los fármacos
16.
Life Sci ; 246: 117399, 2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32032648

RESUMEN

AIMS: Glioblastomas are highly aggressive brain tumors with a very poor survival rate. EEF1A2, the proto-oncogenic isoform of the EEF1A translation factor family, has been found to be overexpressed and promoting tumorigenesis in multiple cancers. Interestingly, recent studies reported reduced expression of this protein in brain tumors, drawing our attention to find the functional role and mechanism of this protein in brain tumor progression. MAIN METHODS: Using representative cell line as models, the role of EEF1A2 in cell proliferation, migration and invasion were assessed using MTS assay, scratch wound-healing assay, transwell migration and invasion assay, respectively. Activation of key signaling pathways was assessed using western blots and real-time PCR. Finally, using immunohistochemistry we checked the protein levels of EEF1A2 in CNS tumors. KEY FINDINGS: EEF1A2 was found to increase the proliferative, migratory and invasive properties of cell lines of both glial and neuronal origin. PI3K activation directly correlated with EEF1A2 levels. Protein levels of key EMT markers viz. Twist, Snail, and Slug were increased upon ectopic EEF1A2 expression. Furthermore, EEF1A2 was found to affect the expression levels of key inflammatory cytokines, growth factors and matrix metalloproteases. IHC analysis showed that EEF1A2 is upregulated in tumor tissues compared to normal tissue. SIGNIFICANCE: EEF1A2 acts as an oncogene in both neuronal and glial cells and triggers an EMT program via PI3K pathway. However, it shows enhanced expression in neuronal cells of the brain than the glial cells, which could explain the previously reported anomaly.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Transición Epitelial-Mesenquimal , Factor 1 de Elongación Peptídica/metabolismo , Western Blotting , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patología , Factor 1 de Elongación Peptídica/fisiología , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcriptoma
17.
Planta Med ; 86(5): 331-337, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32016931

RESUMEN

Metastasis, which is closely linked to cancer-related deaths, is a highly complex process. It is an organ-specific process and involves interactions between the host and cancer cells. CXC chemokine receptor 4 is known to be expressed in various tumors and the binding with CXC ligand 12 induces signaling in cancer cell survival, migration, and proliferation. Particularly, the CXC chemokine receptor 4/CXC ligand 12 axis is known to promote the metastasis of breast cancer. Thus, agents that can downregulate CXC chemokine receptor 4 expression have potential against cancer metastasis. Minecoside is an active compound extracted from Veronica peregrina L. It is widely distributed in Korea and has been used as a traditional drug for the treatment of various chronic diseases. However, the anticancer and anti-inflammatory effects of minecoside have yet to be clarified. In this study, we found that minecoside downregulates constitutive CXC chemokine receptor 4 expression in MDA-MB-231 breast cancer cells. This downregulation also occurred at the transcriptional level. Minecoside-mediated suppression of CXC chemokine receptor 4 expression inhibited CXC ligand 12-induced invasion of breast and colorectal cancer cells. Overall, our results suggest that minecoside can be a novel anticancer agent that can inhibit cancer metastasis through inhibition of CXC chemokine receptor 4 expression.


Asunto(s)
Neoplasias de la Mama , Neoplasias del Colon , Línea Celular Tumoral , Movimiento Celular , Regulación hacia Abajo , Humanos , Invasividad Neoplásica , Receptores CXCR4
18.
Adv Exp Med Biol ; 1202: 129-149, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034712

RESUMEN

Tumor cell invasiveness is a critical challenge in the clinical management of glioma patients. In addition, there is accumulating evidence that current therapeutic modalities, including anti-angiogenic therapy and radiotherapy, can enhance glioma invasiveness. Glioma cell invasion is stimulated by both autocrine and paracrine factors that act on a large array of cell surface-bound receptors. Key signaling elements that mediate receptor-initiated signaling in the regulation of glioblastoma invasion are Rho family GTPases, including Rac, RhoA and Cdc42. These GTPases regulate cell morphology and actin dynamics and stimulate cell squeezing through the narrow extracellular spaces that are typical of the brain parenchyma. Transient attachment of cells to the extracellular matrix is also necessary for glioblastoma cell invasion. Interactions with extracellular matrix components are mediated by integrins that initiate diverse intracellular signalling pathways. Key signaling elements stimulated by integrins include PI3K, Akt, mTOR and MAP kinases. In order to detach from the tumor mass, glioma cells secrete proteolytic enzymes that cleave cell surface adhesion molecules, including CD44 and L1. Key proteases produced by glioma cells include uPA, ADAMs and MMPs. Increased understanding of the molecular mechanisms that control glioma cell invasion has led to the identification of molecular targets for therapeutic intervention in this devastating disease.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Invasividad Neoplásica , Transducción de Señal , Animales , Movimiento Celular , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Integrinas/metabolismo
19.
Adv Exp Med Biol ; 1202: 151-178, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034713

RESUMEN

Protein tyrosine kinases are enzymes that are capable of adding a phosphate group to specific tyrosines on target proteins. A receptor tyrosine kinase (RTK) is a tyrosine kinase located at the cellular membrane and is activated by binding of a ligand via its extracellular domain. Protein phosphorylation by kinases is an important mechanism for communicating signals within a cell and regulating cellular activity; furthermore, this mechanism functions as an "on" or "off" switch in many cellular functions. Ninety unique tyrosine kinase genes, including 58 RTKs, were identified in the human genome; the products of these genes regulate cellular proliferation, survival, differentiation, function, and motility. Tyrosine kinases play a critical role in the development and progression of many types of cancer, in addition to their roles as key regulators of normal cellular processes. Recent studies have revealed that RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Met, Tie, Axl, discoidin domain receptor 1 (DDR1), and erythropoietin-producing human hepatocellular carcinoma (Eph) play a major role in glioma invasion. Herein, we summarize recent advances in understanding the role of RTKs in glioma pathobiology, especially the invasive phenotype, and present the perspective that RTKs are a potential target of glioma therapy.


Asunto(s)
Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Glioma/enzimología , Glioma/patología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular , Proliferación Celular , Glioma/tratamiento farmacológico , Humanos , Fosforilación , Fosfotirosina/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores
20.
Cell Physiol Biochem ; 54(2): 161-179, 2020 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-32045141

RESUMEN

BACKGROUND/AIMS: We performed co-culture experiments between human RPE cells (ARPE-19) and human umbilical vascular endothelial cells (HUVEC) in order to evaluate how anti-VEGF drugs could affect NO release, mitochondrial function, the oxidative status, proliferation and migration of RPE cells through modulation of their cross talk with vascular endothelial cells. METHODS: The co-culture HUVEC/RPE, was exposed to Ranibizumab/Aflibercept in the absence/presence of the NO synthase (NOS) inhibitor, the phosphatidylinositol 3'-kinase (PI3K), the extracellular-signal-regulated kinases 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) blockers. Specific kits were used for cell viability, mitochondrial membrane potential, NO, ROS and GSH production. Western blot was performed for apoptosis markers, NOS isoforms, and others kinases detection. Cell migration was analyzed by scratch assay, whereas cell proliferation and cell cycle through xCELLigence and flow cytometry. RESULTS: In RPE cells co-cultured with HUVEC in physiological conditions, Aflibercept/Ranibizumab increased NO release in a dose and time-dependent way. Opposite results were obtained in peroxidative conditions. Both anti-VEGF agents were able to prevent the fall of cell viability and mitochondrial membrane potential, an effect which was reduced by various inhibitors, and increased cell migration. Aflibercept/Ranibizumab counteracted the changes of apoptosis markers, NOS expression/activation, PI3K and ERK1/2 activation caused by peroxidation. These results were confirmed by cell cycle analysis. CONCLUSION: This study has shown new mechanisms at the basis of protective effects elicited by Aflibercept/Ranibizumab in RPE cells. HUVEC stimulated with Aflibercept/Ranibizumab, could release some paracrine factors that can modulate the RPE cells response in both physiologic and peroxidative conditions.


Asunto(s)
Comunicación Celular/efectos de los fármacos , Ranibizumab/farmacología , Proteínas Recombinantes de Fusión/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Glutatión/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/metabolismo
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