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1.
Chem Biol Interact ; 323: 109063, 2020 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-32224134

RESUMEN

Exposure to TiO2 NPs induces several cellular alterations after NPs uptake including disruption of cytoskeleton that is crucial for lung physiology but is not considered as a footprint of cell damage. We aimed to investigate cytoskeleton disturbances and the impact on cell migration induced by an acute TiO2 NPs exposure (24 h) and the recovery capability after 6 days of NPs-free treatment, which allowed investigating if cytoskeleton damage was reversible. Exposure to TiO2 NPs (10 µg/cm2) for 24 h induced a decrease 20.2% and 25.1% in tubulin and actin polymerization. Exposure to TiO2 NPs (10 µg/cm2) for 24 h followed by 6 days of NPs-free had a decrease of 26.6% and 21.3% in tubulin and actin polymerization, respectively. The sustained exposure for 7 days to 1 µg/cm2 and 10 µg/cm2 induced a decrease of 22.4% and 30.7% of tubulin polymerization respectively, and 28.7% and 46.2% in actin polymerization. In addition, 24 h followed 6 days of NPs-free exposure of TiO2 NPs (1 µg/cm2 and 10 µg/cm2) decreased cell migration 40.7% and 59.2%, respectively. Cells exposed (10 µg/cm2) for 7 days had a decrease of 65.5% in cell migration. Ki67, protein surfactant B (SFTPB) and matrix metalloprotease 2 (MMP2) were analyzed as genes related to lung epithelial function. The results showed a 20% of Ki67 upregulation in cells exposed for 24 h to 10 µg/cm2 TiO2 NPs while a downregulation of 20% and 25.8% in cells exposed to 1 µg/cm2 and 10 µg/cm2 for 24 h followed by 6 days of NPs-free exposure. Exposure to 1 µg/cm2 and 10 µg/cm2 for 24 h and 7 days upregulates SFTPB expression in 53% and 59% respectively, MMP2 expression remain unchanged. In conclusion, exposure of TiO2 NPs affected cytoskeleton of lung epithelial cells irreversibly but this damage was not cumulative.


Asunto(s)
Citoesqueleto/patología , Células Epiteliales/patología , Pulmón/patología , Nanopartículas/toxicidad , Titanio/toxicidad , Células A549 , Actinas/metabolismo , Movimiento Celular/efectos de los fármacos , Tamaño de la Célula , Supervivencia Celular/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Endocitosis , Células Epiteliales/efectos de los fármacos , Células Epiteliales/ultraestructura , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Antígeno Ki-67/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Nanopartículas/ultraestructura , Polimerizacion , Precursores de Proteínas/metabolismo , Proteínas Asociadas a Surfactante Pulmonar/metabolismo , Tubulina (Proteína)/metabolismo
2.
An Acad Bras Cienc ; 92(1): e20181127, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32321021

RESUMEN

Obesity is characterized by the excess of body fat and, therefore, may cause musculoskeletal alterations that can negatively influence the tendons. Such overweight-influenced alterations are exercise sensitive though. Morphological and biochemical alterations were reported in the calcaneal tendon of mice submitted to a lipid-rich diets along with practicing exercises, with the following groups: normal diet without exercise (ND), normal diet with exercise (NDex), lipid-rich diet without exercise (LD), lipid-rich diet without exercise (LDex). The calcaneal tendons were removed and subjected to histological and biochemical analysis. Layers of the tissue were stained with Hematoxylin and Eosin, Picrosirius Red and Von Kossa while a protein dosage was conduce by the Bradford method. The morphologicals analysis there was no statistical difference concerning the number of fibroblasts among the groups. Groups submitted to exercises showed higher amount of collagen and non-collagenous protein deposition. The lipid-rich diet without exercse group had a more disorganized collagen matrix with intense basophilia. The same group had areas of calcification confirmed by Von Kossa technique. Practicing physical activity, such as swimming, can improve the changes caused in the calcaneal tendon in mice submitted to a lipid-rich diets, having a better collagen organization and the synthesis.


Asunto(s)
Tendón Calcáneo/metabolismo , Colágeno/metabolismo , Grasas de la Dieta/metabolismo , Lípidos/administración & dosificación , Metaloproteinasa 2 de la Matriz/metabolismo , Condicionamiento Físico Animal , Natación , Animales , Grasas de la Dieta/administración & dosificación , Masculino , Ratones
3.
Medicine (Baltimore) ; 99(17): e19822, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32332626

RESUMEN

Previous studies have shown androgen receptor (AR) is associated with the occurrence, development, recurrence, metastasis, and prognosis of triple negative breast cancer (TNBC). More and more experts have noticed that AR signaling pathway plays an important role in the occurrence and development of TNBC. The purpose of this study is to detect the inhibitory efficacy and mechanism of Bicalutamide on the proliferation and invasion of TNBC cells.MDA-MB-231 cells of human breast cancer cells were treated with 0, 25, 100 µmol/L of Bicalutamide, cell proliferation assay was performed to assess cell proliferation viability by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide assay and cell invasion was evaluated by Transwell assay. Meanwhile, flow cytometric analysis and western blotting were performed to investigate the mechanism of Bicalutamide on the proliferation and invasion of MDA-MB-231 cells.Bicalutamide could efficiently inhibit the proliferation and invasion of MDA-MB-231 cells in a dose-dependent manner. In addition, Bicalutamide could significantly induce the cell cycle arrest at G0/G1 phase and decrease the protein expression of AR, cyclin D1, matrix metalloprotease-2 (MMP-2), and matrix metalloprotease-9 (MMP-9).The present study indicated the Bicalutamide inhibited the proliferation and invasion process of triple negative breast cancer cells by targeting AR signaling pathway and down-regulating MMP-2/-9 protein expression levels.


Asunto(s)
Anilidas/uso terapéutico , Proliferación Celular/efectos de los fármacos , Nitrilos/uso terapéutico , Compuestos de Tosilo/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Anilidas/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo/métodos , Humanos , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Nitrilos/farmacología , Sales de Tetrazolio , Compuestos de Tosilo/farmacología , Neoplasias de la Mama Triple Negativas/fisiopatología
4.
Life Sci ; 250: 117554, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32184123

RESUMEN

BACKGROUND: Mental stress (MS) is related to endothelial dysfunction in overweight/obese men. It is believed that the pro-oxidant profile, associated with an imbalance in the vascular remodeling process, may contribute to deleterious effects of MS on endothelial function. However, it is unknown whether administration of ascorbic acid (AA), a potent antioxidant, can prevent oxidative and remodeling dysfunction during MS in these subjects. METHODS: Fourteen overweight/obese grade I men (27 ± 7 years; 29.7 ± 2.6 kg·m-2) underwent the Stroop Color Word Test for 5 min to induce MS after AA (3 g) or placebo (PL, 0.9% NaCl) intravenous infusions. Venous blood samples were collected at baseline and the last minute of MS to measure nitrite concentration (chemiluminescence), protein carbonylation, thiobarbituric acid reactive substances (TBARS) and catalase activity (colorimetric assays), superoxide dismutase (SOD; immunoenzymatic assay), activities of active/inactive (pro) forms of metalloproteinases-9 and -2 (MMP; zymography) and its respective tissue inhibitors concentration (TIMP-1 and TIMP-2; immunoenzymatic assays). RESULTS: At baseline, MMP-9 activity (p < 0.01), the MMP-9/proMMP-9 ratio (p = 0.02) and TIMP-1 concentration (p = 0.05) were reduced, whereas proMPP-9 activity was increased (p = 0.02) after AA compared to PL infusion. After PL infusion, MS increased protein carbonylation (p < 0.01), catalase (p < 0.01), and the MMP-9/proMMP-9 ratio (p = 0.04) when compared to baseline. AA infusion reduced protein carbonylation (p = 0.02), MMP-9 activity (p < 0.01), and MMP-9/pro-MMP-9 ratio (p < 0.01), while SOD (p = 0.04 vs baseline), proMPP-9 (p < 0.01 vs PL), MMP-2 (p < 0.01 vs PL) and TIMP-2 (p = 0.02 vs baseline) remained elevated during MS. CONCLUSIONS: AA appears to minimize the oxidative imbalance and vascular remodeling induced by MS.


Asunto(s)
Ácido Ascórbico/farmacología , Obesidad/psicología , Sobrepeso/psicología , Estrés Psicológico , Remodelación Vascular/efectos de los fármacos , Adulto , Antioxidantes/metabolismo , Catalasa/metabolismo , Estudios Cruzados , Endotelio Vascular/patología , Humanos , Luminiscencia , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Oxidantes/metabolismo , Carbonilación Proteica , Factores de Riesgo , Test de Stroop , Superóxido Dismutasa/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Adulto Joven
5.
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
6.
Biosci Trends ; 14(1): 23-34, 2020 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-32092745

RESUMEN

The roots of Angelica dahurica have long been used as a traditional medicine in Korea to treat various diseases such as toothache and cold. In this study, we investigated the effect of ethanol extract from the roots of this plant on metastatic melanoma, a highly aggressive skin cancer, in B16F10 melanoma cells and B16F10 cell inoculated-C57BL/6 mice. Our results showed that the ethanol extracts of Angelicae dahuricae Radix (EEAD) suppressed cell growth and induced apoptotic cell death in B16F10 cells. EEAD also activated the mitochondria-mediated intrinsic apoptosis pathway, with decreased mitochondrial membrane potential, and increased production of intracellular reactive oxygen species and ration of Bax/Bcl-2 expression. Furthermore, EEAD reduced the migration, invasion, and colony formation of B16F10 cells through the reduced expression and activity of matrix metalloproteinase (MMP)-2 and -9. In addition, in vivo results demonstrated that oral administration of EEAD inhibited lactate dehydrogenase activity, hepatotoxicity, and nephrotoxicity without weight loss in B16F10 cell inoculated-mice. Importantly, EEAD was able to markedly suppress lung hypertrophy, the incidence of B16F10 cells lung metastasis, and the expression of tumor necrosis factor-alpha in lung tissue. Taken together, our findings suggest that EEAD may be useful for managing metastasis and growth of malignant cancers, including melanoma.


Asunto(s)
Angelica/química , Melanoma Experimental/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Apoptosis , Línea Celular Tumoral , Hipertrofia , L-Lactato Deshidrogenasa/antagonistas & inhibidores , Pulmón/patología , Neoplasias Pulmonares , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , Metástasis de la Neoplasia/prevención & control , Raíces de Plantas/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteína X Asociada a bcl-2/metabolismo
7.
Am J Physiol Heart Circ Physiol ; 318(3): H508-H518, 2020 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-31975626

RESUMEN

Cigarette smoking is a major risk factor for aortic aneurysm and dissection; however, no causative link between smoking and these aortic disorders has been proven. In the present study, we investigated the mechanism by which cigarette smoke affects vascular wall cells and found that cigarette smoke extract (CSE) induced a novel form of regulated cell death termed ferroptosis in vascular smooth muscle cells (VSMCs). CSE markedly induced cell death in A7r5 cells and primary rat VSMCs, but not in endothelial cells, which was completely inhibited by specific ferroptosis inhibitors [ferrostatin-1 (Fer-1) and Liproxstatin-1] and an iron chelator (deferoxamine). CSE-induced VSMC death was partially inhibited by a GSH precursor (N-acetyl cysteine) and an NADPH oxidase inhibitor [diphenyleneiodonium chloride (DPI)], but not by inhibitors of pan-caspases (Z-VAD), caspase-1 (Z-YVAD), or necroptosis (necrostatin-1). CSE also upregulated IL-1ß, IL-6, TNF-α, matrix metalloproteinase (MMP)-2, MMP-9, and TIMP-1 (tissue inhibitor of metalloproteinase)in A7r5 cells, which was inhibited by Fer-1. Furthermore, CSE induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. VSMC ferroptosis was induced by acrolein and methyl vinyl ketone, major constituents of CSE. Furthermore, CSE caused medial VSMC loss in ex vivo aortas. Electron microscopy analysis showed mitochondrial damage and fragmentation in medial VSMCs of CSE-treated aortas. All of these manifestations were partially restored by Fer-1. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death and suggest that ferroptosis is a potential therapeutic target for preventing aortic aneurysm and dissection.NEW & NOTEWORTHY Cigarette smoke extract (CSE)-induced cell death in rat vascular smooth muscle cells (VSMCs) was completely inhibited by specific ferroptosis inhibitors and an iron chelator. CSE also induced the upregulation of Ptgs2 mRNA, lipid peroxidation, and intracellular GSH depletion, which are key features of ferroptosis. CSE caused medial VSMC loss in ex vivo aortas. These findings demonstrate that ferroptosis is responsible for CSE-induced VSMC death.


Asunto(s)
Ferroptosis/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Humo , Animales , Muerte Celular/efectos de los fármacos , Línea Celular , Ciclohexilaminas/farmacología , Deferoxamina/farmacología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , NADPH Oxidasas/metabolismo , Fenilendiaminas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Sideróforos/farmacología , Compuestos de Espiro/farmacología , Inhibidor Tisular de Metaloproteinasa-1/metabolismo
8.
Chem Biol Interact ; 315: 108864, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31629700

RESUMEN

Type II diabetes is recognized as a major risk factor for death due to cardiovascular complications such as coronary heart disease (CHD), but the complex interplay between these two diseases remains poorly understood. Suppression of oxidative stress, apoptosis, and inflammation of endothelial cells is a valuable treatment strategy to prevent or halt the progression of CHD. In the present study, we used real-time polymerase chain reaction (PCR), Western blot analysis, and enzyme linked immunosorbent assay (ELISA) to investigate the effects of saxagliptin on hypoxia-inducible factors. Our findings demonstrate that saxagliptin can significantly improve cell viability in H9c2 cells as well as reduce hypoxia-induced oxidative damage and loss of mitochondrial membrane potential. Saxagliptin reduced hypoxia-induced NADPH oxidase 4 (NOX 4). We also show that saxagliptin can reduce the expression of matrix metallopeptidase-2 (MMP-2) and matrix metallopeptidase-9 (MMP-9), two important degradative enzymes. Saxagliptin also suppressed hypoxia-induced expression of high mobility group box-1 protein (HMGB1), a key inflammatory cytokine. Finally, we show that saxagliptin can exert atheroprotective effects by reducing the expression of myeloid differential protein-88 (MyD88) and increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Thus, saxagliptin shows promise as a treatment against diabetes-associated CHD.


Asunto(s)
Adamantano/análogos & derivados , Dipéptidos/farmacología , Hipoxia/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Adamantano/farmacología , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Proteína HMGB1/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hipoxia/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , NADPH Oxidasa 4/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Transducción de Señal/efectos de los fármacos
9.
Chem Biol Interact ; 315: 108901, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31733186

RESUMEN

Chondrocytes in joints are responsible for the formation and remodeling of articular cartilage. The accumulation of advanced glycation end products (AGEs) in cartilage is detrimental to the survival of chondrocytes. Linagliptin is one of the most commonly used anti-diabetes agents, and recent work indicates that it exerts an anti-inflammatory effect in different cell types. In this study, we showed that Linagliptin had a protective role in AGEs-induced chondrocyte injury. The presence of Linagliptin ameliorated AGEs-induced reactive oxygen species (ROS) induction and reduced cellular protein carboxyl content. Linagliptin mitigated AGEs-induced mitochondrial membrane potential (ΔΨm) reduction and NAPDH oxidase subunit NOX-4 induction, indicating that Linagliptin is a potent anti-ROS agent in chondrocytes. Additionally, Linagliptin inhibited AGEs-induced production of high mobility group box chromosomal protein 1 (HMGB-1), and the expression of matrix metalloproteases (MMPs)-2 and -9. Flow cytometry experimentation showed that Linagliptin inhibited AGEs-induced apoptotic subpopulation. Moreover, Linagliptin inhibited the AGEs-induced increased ratio of Bax to Bcl-2, translocation of cytochrome C from mitochondria to the cytoplasm, and release of cleaved caspase-3. Collectively, our data indicate that the anti-diabetes drug Linagliptin has a new role in rescuing chondrocyte from insult by AGEs, and may, therefore, have the potential to treat joint disorders.


Asunto(s)
Apoptosis/efectos de los fármacos , Condrocitos/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Linagliptina/farmacología , Mitocondrias/efectos de los fármacos , Sustancias Protectoras/farmacología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Caspasa 3/metabolismo , Línea Celular , Condrocitos/metabolismo , Citocromos c/metabolismo , Citoplasma/efectos de los fármacos , Citoplasma/metabolismo , Proteína HMGB1/metabolismo , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo
10.
Chem Biol Interact ; 316: 108915, 2020 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-31816286

RESUMEN

Stroke has been considered the second leading cause of death worldwide, and ischemic stroke accounts for the vast majority of stroke cases. Some of the main features of ischemic stroke are increased brain permeability, ischemia/reperfusion injury, oxidative stress, and acute inflammation. Antagonism of cysLT1R has been shown to provide cardiovascular and neural benefits. In the present study, we investigated the effects of the cysLT1R antagonist zafirlukast both in vivo and in vitro using a middle cerebral artery occlusion (MCAO) mouse model and human brain microvascular endothelial cells (HBMVECs). In vivo, we found that zafirlukast pretreatment could reduce MCAO-induced increased brain permeability by rescuing the expression levels of the tight junction proteins occludin and ZO-1. In vitro, we found that zafirlukast could suppress the increase in endothelial monolayer permeability induced by OGD/R via rescue of occludin and ZO-1 expression; additionally, we found that zafirlukast prevented OGD/R-induced degradation of the extracellular matrix via inhibition of MMP-2 and MMP-9 expression. Finally, we found that zafirlukast could also inhibit OGD/R-induced activation of the critical proinflammatory regulator NF-κB by preventing phosphorylation and nuclear translocation of p65 protein. Together, our findings demonstrate a promising role for zafirlukast in preventing damage induced by ischemic stroke and reperfusion injury.


Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Compuestos de Tosilo/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Infarto Encefálico/etiología , Infarto Encefálico/prevención & control , Permeabilidad de la Membrana Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/patología , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Ocludina/genética , Ocludina/metabolismo , Compuestos de Tosilo/uso terapéutico , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismo
11.
Life Sci ; 244: 117153, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31830479

RESUMEN

AIMS: Increased activity of calpain-1 and matrix metalloproteinase (MMP)-2 was observed in different models of arterial hypertension and contribute to thicken the left ventricle (LV) walls and to hypertrophy cardiac myocytes. MMP-2 activity may be regulated by calpain-1 via bioactive molecules activation such as transforming growth factor (TGF)-ß in cardiovascular diseases. This study analyzed whether calpain-1 causes cardiac hypertrophy and dysfunction by modulating the expression and activity of MMP-2 in renovascular hypertension. MAIN METHODS: Male Wistar rats were submitted to two kidneys, one clip (2K1C) model of hypertension or sham surgery and were treated with verapamil (VRP, 8 mg/kg/bid) by gavage from the second to tenth week post-surgery. Systolic blood pressure (SBP) was weekly assessed by tail-cuff plethysmography and morphological and functional parameters of LV were analyzed by echocardiography. MMP-2 activity was analyzed by in situ and gelatin zymography, while calpain-1 activity by caseinolytic assay. MMP-2, calpain-1, TGF-ß and MMP-14/TIMP-2 levels were identified in the LV by western blots. Fluorescence assays were performed to evaluate oxidative stress, MMP-2 and calpain-1 levels. KEY FINDINGS: SBP increased in 2K1C rats and was unaltered by VRP. However, VRP notably ameliorated hypertension-induced increase in LV thickness. VRP decreased hypertension-induced enhances in calpain-1 and MMP-2 activities, oxidative stress and mature TGF-ß levels. Treatment with VRP also decreased the accentuated MMP-14/TIMP-2 levels in 2K1C. SIGNIFICANCE: Treatment with VRP decreases calpain-1 and MMP-2 activities and also reduces TGF-ß and MMP-14/TIMP-2 levels in the LV of hypertensive rats, thus contributing to ameliorate cardiac hypertrophy.


Asunto(s)
Calpaína/metabolismo , Cardiomegalia/tratamiento farmacológico , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión/complicaciones , Metaloproteinasa 2 de la Matriz/metabolismo , Remodelación Ventricular/efectos de los fármacos , Verapamilo/farmacología , Animales , Calpaína/genética , Cardiomegalia/etiología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Ratas , Ratas Wistar , Vasodilatadores/farmacología
12.
Biol Cell ; 112(3): 73-91, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31879982

RESUMEN

BACKGROUND INFORMATION: Piwi-interacting RNAs (piRNAs) are a novel class of ∼23-36 nts long endogenous small non-coding RNAs, earlier known to maintain germline genome integrity during development by regulating transposable elements. Recently, piRNAs are known to regulate cell proliferation, apoptosis and metastasis in different cancer cells. However, piRNAs have not yet been reported in human osteosarcoma (OS), a highly metastatic aggressive bone tumour among adolescents. Therefore, our current study aimed to decrypt the potential role of a piRNA, piR-39980 in osteosarcoma, which was earlier reported by us in fibrosarcoma, neuroblastoma and epithelial ovarian cancer. RESULTS: We found that piR-39980 is significantly upregulated in two human osteosarcoma cell lines, 143B and HOS compared to IMR90-tert fibroblast cells. The transient overexpression of endogenous piR-39980 level through transfection by piRNA mimic promotes proliferation, migration and invasion ability of OS cells, whereas its inhibition significantly induces apoptosis, chromatin condensation and γ-H2AX accumulation as well as restrains migration and invasion of OS cells. Further, we found 13 genes as targets of piR-39980 using miRanda, among which SERPINB1 that is downregulated in OS cells is seen to suppress proliferation, and migration in this cancer upon its overexpression. The knockdown of piR-39980 in OS cells led to enhanced expression of SERPINB1 indicating to be its target, which was then confirmed by dual luciferase reporter assay. In addition, gelatin zymography and western blotting revealed that transfection of piR-39980 mimic promotes MMP-2 activation, whereas its inhibition and SERPINB1 overexpression suppresses MMP-2 activation in OS cells. CONCLUSIONS: Taken together, our study revealed that piR-39980 promotes migration and invasion via MMP-2 activation as well as inhibits cell death, both through negative regulation of SERPINB1. SIGNIFICANCE: This study revealed that piR-39980 functions as an oncogene in human osteosarcoma, which could be harnessed as a potential therapeutic target for this malignancy.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 2 de la Matriz/metabolismo , Osteosarcoma/metabolismo , ARN Interferente Pequeño/genética , Serpinas/metabolismo , Apoptosis/genética , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , Metaloproteinasa 2 de la Matriz/genética , MicroARNs/genética , Oncogenes/genética , Osteosarcoma/genética , Serpinas/genética
13.
Biosci Biotechnol Biochem ; 84(1): 103-110, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31559912

RESUMEN

We previously reported that MDA-MB-231 and MCF-7 cells, which are breast cancer cell lines and have cancer and cancer-initiating cells (CICs), were killed following normothermic microwave irradiation in which the cellular temperature was maintained at 37°C. In this study, we investigated the percentages of live or dead cells among CD44+/CD24- cells, which were defined as CICs among MDA-MB-231 and MCF-7 cells, and other types of cells in response to microwave irradiation. CD44+/CD24- cells among MDA-MB-231 cells were killed, thereby decreasing the number of cells, whereas the number of live CD44+/CD24- MCF-7 cells was increased following microwave irradiation. Moreover, adhesion, invasion, and migration were decreased in MDA-MB-231 cells, and the activation of matrix metalloproteinase-2 (MMP-2) in MDA-MB-231 cells was increased following microwave irradiation. These decreased cell activities might have been caused by MMP-2 activation and population changes in CD44+/CD24- in MDA-MB-231 cells.Abbreviations: APC: allophecocyanin; CBB: coomassie Brilliant Blue; CD: cluster of differentiation; CICs: cancer-initiating cells; FACS: fluorescence-activated cell sorting; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; FTDT: finite-difference time domain; HER2: human epidermal growth factor receptor type 2; PI: propidium iodide.


Asunto(s)
Antígeno CD24/metabolismo , Adhesión Celular/efectos de la radiación , Movimiento Celular/efectos de la radiación , Receptores de Hialuranos/metabolismo , Microondas , Neoplasias de la Mama Triple Negativas/patología , Apoptosis/efectos de la radiación , Recuento de Células , Colorantes/metabolismo , Femenino , Citometría de Flujo , Humanos , Células MCF-7 , Metaloproteinasa 2 de la Matriz/metabolismo , Invasividad Neoplásica , Propidio/metabolismo , Temperatura
14.
Arch Oral Biol ; 109: 104583, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31706109

RESUMEN

OBJECTIVE: In this study, the aim was to investigate the biochemical, physiological and histological changes that occur in masticatory muscles of the masticatory system with aging. DESIGN: In this study, 14 BALB/c mice were used. Animals were divided into two equal groups of seven. Group I was organized as the group of young animals (n = 7) and Group II as the group of adult animals (n = 7). After routine histological follow-up was performed, the tissues were embedded in paraffin. 4-5 µm thick cross-sections were taken from paraffin-embedded tissues and they were stained with Haemotoxylin and Eosin Type I collagen and Matrix metalloproteinase-2 (MMP-2) immunohistochemically. RESULTS: It was observed that there was a decrease and shrinking in blood vessels due to aging. In young mice, Type I collagen and MMP-2 immunoreactivity in the masseter muscle tissue showed low staining, while Type I collagen and MMP-2 immunoreactivity in the temporal muscle tissue showed moderate staining. Type I collagen and MMP-2 immunoreactivity were significantly higher in the masseter and temporal muscles of elderly mice (p = 0.001). In the H-score evaluation, MMP-2 immune reactivity was significantly lower in young mice than in older mice (p = 0.001). CONCLUSION: It was determined that severe pain complications and functional losses are likely to occur with the increase of degeneration due to aging of masticator muscles.


Asunto(s)
Envejecimiento , Colágeno Tipo I/metabolismo , Músculos Masticadores/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Animales , Masticación , Ratones , Ratones Endogámicos BALB C
15.
Yonsei Med J ; 61(1): 85-93, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31887804

RESUMEN

PURPOSE: The aim of this study was to investigate the effect of FST gene on the inhibition of fibrosis in fibroblastic cells from scar tissue around repaired zone II flexor tendons. MATERIALS AND METHODS: Immunohistochemistry was conducted on fibroblast cells transfected with adenovirus-LacZ (Ad-LacZ) as a marker gene (control), or with adenovirus-FST (Ad-FST) as a therapeutic gene. Fibroblast cultures without adenoviral exposure served as controls. RESULTS: Fibroblastic cells transfected with Ad-FST demonstrated significant decrease in collagen type I, MMP-1, MMP2, and α-SMA mRNA expressions compared to those transfected with Ad-LacZ. In addition, fibroblastic cells transfected with Ad-FST exhibited significant decrease in MMP-1, TIMP-1, fibronectin, PAI-1, TRPV4, α-SMA, desmin, and PAX7 protein expressions. CONCLUSION: Based on these findings, we conclude that FST may be a novel therapeutic strategy for preventing scar adhesions around repaired tendons by inhibiting fibroblasts from differentiating into myofibroblasts, in addition to producing type I collagen and regulating extracellular matrix turnover via the downregulation of MMP-1 and TIMP-1. FST may also decrease contracture of the scar by inhibiting Ca2+-dependent cell contraction.


Asunto(s)
Diferenciación Celular/efectos de los fármacos , Cicatriz/metabolismo , Cicatriz/patología , Colágeno Tipo I/biosíntesis , Fibroblastos/metabolismo , Folistatina/metabolismo , Miofibroblastos/patología , Traumatismos de los Tendones/patología , Actinas/metabolismo , Animales , Células Cultivadas , Desmina/metabolismo , Femenino , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrosis , Regulación de la Expresión Génica , Humanos , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Factor de Transcripción PAX7/genética , Factor de Transcripción PAX7/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo , Tendones/patología
16.
Mater Sci Eng C Mater Biol Appl ; 107: 110212, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31761208

RESUMEN

A critical challenge to the development of tissue engineering small-diameter vascular grafts is to achieve rapid endothelialization and long-term anticoagulation. It is necessary to graft both adhesion and antithrombus factors onto the surface of polycaprolactone without burst release to promote endothelial cell affinity and antithrombogenicity. A bionic structure with a nanocoating that allows a biologically responsive, long-term release was employed in this work to enable the grafting of various bioactive molecules such as gelatin, polylysine, and heparin. This approach involved orienting the biomimetic vascular structures; the self-assembly grafting of gelatin, polylysine, and heparin nanoparticles; and genipin crosslinking to form a multiphase crosslinked nanocoating. In this biologically inspired design, vascular endothelialization and long-term anticoagulation were successfully induced through a matrix metallopeptidase 2 regulative mechanism by delivering both adhesion and antithrombus factors with a responsive, long-term release without burst release. The method provided a simple and effective approach for delivering dual factors for tissue engineering small-diameter vascular grafts.


Asunto(s)
Materiales Biomiméticos/química , Nanotecnología , Materiales Biomiméticos/farmacología , Coagulación Sanguínea/efectos de los fármacos , Plaquetas/citología , Prótesis Vascular , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Gelatina/química , Heparina/química , Heparina/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Metaloproteinasa 2 de la Matriz/química , Metaloproteinasa 2 de la Matriz/metabolismo , Nanofibras/química , Poliésteres/química , Polilisina/química , Propiedades de Superficie
17.
J Ethnopharmacol ; 246: 111768, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-30849507

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma wenyujin Y.H. (CW), a variety of Curumae Rhizoma, which documented in China Pharmacopeia, has long been used as plant medicine for its traditional effect on promoting Qi, activating blood stagnation and expelling blood stasis. Nowadays, it is often used in clinic for extraordinary effect on liver diseases. It is worthy to be noted that CW processed with vinegar has been applied in clinic for 1500 years which started in the northern and southern dynasties. AIM OF STUDY: Liver fibrosis is a worldwide clinical issue. It is worth developing a multi-target and multicellular approach which is high efficiency and low side effects for the treatment of hepatic fibrosis. The anti-hepatic fibrosis molecular mechanisms of CW and vinegar Curcuma wenyujin (VCW) need to be explored and elucidated. Furthermore, the study aimed to discuss the efficiency and mechanism differences between CW and VCW in hepatic fibrosis. METHODS AND RESULTS: Biochemical assays and histopathology were adopted to evaluate the anti-hepatic fibrosis effect of CW and VCW. The TGF-ß/Smad signaling involving TGF-ß1, TGF-ßRⅠ, TGF-ßRⅡ and Smad2, Smad3, Smad7 in fibrosis is examined, which is a critical step towards the evaluation of anti-hepatic fibrosis agents. Meanwhile, the MMP/TIMP balance is a potential therapy target by modulating extracellular matrix, which is also examined. Both CW and VCW inhibit the activation and proliferation of hepatic stellate cells and induce apoptosis via blocking TGF-ß/Smad signaling pathways. Additionally, the level of MMP-2/TIMP-1 regulated significantly, which suggest CW and VCW participate in the degradation process, and maintain the formation and production of extracellular matrix. CONCLUSION: Raw and vinegar processed Curcuma wenyujin regulates hepatic fibrosis via bloking TGF-ß/Smad signaling pathways and up-regulation of MMP-2/TIMP-1 ratio. And VCW has more exhibition than CW.


Asunto(s)
Curcuma , Cirrosis Hepática/metabolismo , Extractos Vegetales/farmacología , Ácido Acético/química , Animales , Línea Celular , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína smad3/genética , Proteína smad3/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo
18.
Phytomedicine ; 66: 153112, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31786318

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC) spreads further with continuance and increasing incidence due to its high-grade malignancy and metastasis. More effectual strategies on blocking proliferation and metastasis of cancer cells should be studied in HCC. Dulcitol, a natural product extracted from euonymus alatus, was reported that it could induce apoptosis of C6 glioma cells. However, the underlying mechanism of Dulcitol on HCC remains unclea. PURPOSE: In this study, we aimed to reveal the effect and potential mechanisms of Dulcitol on hepatocellular carcinoma in vitro and in vivo. Study design and methods The cell proliferation and apoptosis were evaluated by MTT, Ki-67 and Hoechst 33258/PI double staining. The migratory and invasive abilities of HepG2 cells were measured by wound-healing and transwell assays. Pathological changes of tumor tissue were observed by HE staining and IHC methods. The expression levels of protein were detected using Western Blot analysis. RESULTS: The results showed that Dulcitol inhibited HepG2 cells proliferation by down-regulating the protein expression of SIRT1, Bcl-2, along with up-regulating p53, acetylated-p53 (K382), cleaved-caspase9, cleaved-caspase3, Bax, and cytochrome c in a dose-dependent manner. Furthermore, Dulcitol surpressed the migration and invasion of HepG2 cells through decreasing the levels of MMP-2, uPA and MMP-9 and increasing E-cadherin associated with tumor invasion. In vivo, Dulcitol distinctly inhibited the growth of HepG2 cancer xenograft tumors via inhibiting SIRT1/p53 pathway. CONCLUSIONS: Our findings suggested that Dulcitol acted as a SIRT1 inhibitor, inducing apoptosis and inhibiting proliferation, migration and invasion of HepG2 cells and its modulatory mechanism seemed to be associated with regulation of MMPs, SIRT1/p53 pathways.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Galactitol/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Sirtuina 1/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo , Células Hep G2 , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(10): 1180-1185, 2019 Oct 30.
Artículo en Chino | MEDLINE | ID: mdl-31801717

RESUMEN

OBJECTIVE: To investigate the inhibitory effect of polysaccharide of Atractylodes macrocephala (PAM) on the proliferation and invasion of hepatocellular carcinoma cells and the underlying mechanism. METHODS: Hepatocellular carcinoma HepG2 cells were treated with different concentrations of PAM, and their proliferation and invasive ability were examined using CCK-8 assay and Transwell assay. Immunofluorescence assay was performed to detect the expression level of ß-catenin, and real-time PCR and Western blotting were used to detect the mRNA and protein expressions of AKT, GSK-3ß and MMP-2 in the cells. The changes in the proliferation, invasiveness and the expressions of pGSK-3ß and MMP2 were examined in the cells following treatment with LiCl/PAM/LiCl plus PAM. RESULTS: PAM treatment significantly reduced the cell viability, the number of migration cells, and the expression levels of ß-catenin and MMP-2 (P < 0.05), and obviously inhibited the phosphorylation of AKT and GSK-3ß in the cells (P < 0.05) in a dose-dependent manner. The rescue experiment showed that LiCl reversed the inhibition of cell proliferation, invasiveness, and the Wnt/ß-catenin pathway induced by PAM. CONCLUSIONS: PAM can inhibit the proliferation and invasion of hepatocellular carcinoma cells in vitro possibly by inhibiting the Wnt/ß-catenin signaling pathway.


Asunto(s)
Atractylodes/química , Carcinoma Hepatocelular/patología , Proliferación Celular/efectos de los fármacos , Neoplasias Hepáticas/patología , Polisacáridos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/metabolismo , Invasividad Neoplásica , Fitoquímicos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vía de Señalización Wnt/efectos de los fármacos
20.
Integr Cancer Ther ; 18: 1534735419890917, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31855073

RESUMEN

Background: Current treatment of osteosarcoma is limited in part by side effects and low tolerability, problems generally avoided with traditional Chinese medicine. Ganoderma lucidum, a traditional Chinese medicine with antitumor effects, offers a potential alternative, but little is known about its molecular mechanisms in osteosarcoma cells. Objective: To investigate the effect of G lucidum on osteosarcoma cells and its mechanism. Methods: Osteosarcoma MG63 and U2-OS cells were treated with G lucidum, followed by assays for cell proliferation (Cell Counting Kit-8), colony formation, and apoptosis (Alexa Fluor 647-Annexin V/propidium iodide, flow cytometry). Migration and invasion of cells were assessed by wound healing and Transwell invasion assays, and the effect of G lucidum on Wnt/ß-catenin signal transduction was studied by real-time quantitative polymerase chain reaction, western blot, and dual-luciferase assay. Results: G lucidum inhibited the proliferation, migration, and invasion, and induced apoptosis of human osteosarcoma MG63 and U2-OS cells. Dual-luciferase assay showed that G lucidum suppressed the transcriptional activity of T-cell factor/lymphocyte enhancer factor in the Wnt/ß-catenin signaling pathway. Moreover, G lucidum blocked Wnt/ß-catenin signaling by inhibiting the Wnt co-receptor LRP5 and Wnt-related target genes, such as ß-catenin, cyclin D1, C-Myc, MMP-2, and MMP-9. At the same time, when Wnt/ß-catenin was inhibited, the expression of E-cadherin was upregulated. Conclusions: Our results suggest that G lucidum broadly suppresses osteosarcoma cell growth by inhibiting Wnt/ß-catenin signaling.


Asunto(s)
Productos Biológicos/farmacología , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Reishi/química , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo
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