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1.
Int J Nanomedicine ; 16: 1961-1976, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33727809

RESUMEN

Introduction: Metastatic breast cancer seriously harms women's health and is currently the tumour type with the highest mortality rate in women. Recently, the combinatorial therapeutic approaches that integrate anti-cancer drugs and genetic agents is an attractive and promising strategy for the treatment of metastatic breast cancer. Moreover, such a combination strategy requires better drug carriers that can effectively deliver the cargo to the breast cancer cells and achieve controlled release in the cells to achieve better therapeutic effects. Methods: The tumour-targeted and redox-responsive mesoporous silica nanoparticles (MSNs) functionalised with DNA aptamers (AS1411) as a co-delivery system was developed and investigated for the potential against metastatic breast cancer. Doxorubicin (Dox) was loaded onto the MSNs, while AS1411 and a small interfering RNA (siTIE2) were employed as gatekeepers via attachment to the MSNs with redox-sensitive disulfide bonds. Results: The controlled release of Dox and siTIE2 was associated with intracellular glutathione. AS1411 mediated the targeted delivery of Dox by increasing its cellular uptake in metastatic breast cancer, ultimately resulting in a lower IC50 in MDA-MB-231 cells (human breast cancer cell line with high metastatic potency), improved biodistribution in tumour-bearing mice, and enhanced in vivo anti-tumour effects. The in vitro cell migration/invasion assay and in vivo anti-metastatic study revealed synergism in the co-delivery system that suppresses cancer cell metastasis. Conclusion: The tumour-targeted and redox-responsive MSN prepared in this study are promising for the effective delivery and controlled release of Dox and siTIE2 for improved treatment of metastatic breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Nanopartículas/química , ARN Interferente Pequeño/administración & dosificación , Dióxido de Silicio/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Preparaciones de Acción Retardada/farmacología , Preparaciones de Acción Retardada/uso terapéutico , Doxorrubicina/farmacología , Portadores de Fármacos/química , Endocitosis/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/ultraestructura , Invasividad Neoplásica , Metástasis de la Neoplasia , Oxidación-Reducción , Porosidad , ARN Interferente Pequeño/farmacología , Distribución Tisular/efectos de los fármacos
2.
Molecules ; 26(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670371

RESUMEN

Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding process. The stability and dynamic properties of systems elucidate the inherent factors of the conformation selection mechanism. Binding free energy analysis quantitatively confirms key interface residues and guide optimization. This study elucidates the conformation selection mechanism in APC-Asef inhibition and provides insights into peptide-based drug design.


Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Péptidos/química , Proteína de la Poliposis Adenomatosa del Colon/química , Proteína de la Poliposis Adenomatosa del Colon/genética , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Ligandos , Simulación de Dinámica Molecular , Metástasis de la Neoplasia , Péptidos/antagonistas & inhibidores , Unión Proteica/efectos de los fármacos , Factores de Intercambio de Guanina Nucleótido Rho/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido Rho/química , Factores de Intercambio de Guanina Nucleótido Rho/genética
3.
J Med Chem ; 64(3): 1713-1724, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33523653

RESUMEN

Carbonic anhydrase IX (CAIX) is considered a target for therapeutic intervention in solid tumors. In this study, the efficacy of the inhibitor, 4-(3-(2,4-difluorophenyl)-oxoimidazolidin-1-yl)benzenesulfonamide (SLC-149), is evaluated on CAIX and a CAIX-mimic. We show that SLC-149 is a better inhibitor than acetazolamide against CAIX. Binding of SLC-149 thermally stabilizes CAIX-mimic at lower concentrations compared to that of CAII. Structural examinations of SLC-149 bound to CAIX-mimic and CAII explain binding preferences. In cell culture, SLC-149 is a more effective inhibitor of CAIX activity in a triple-negative breast cancer cell line than previously studied sulfonamide inhibitors. SLC-149 is also a better inhibitor of activity in cells expressing CAIX versus CAXII. However, SLC-149 has little effect on cytotoxicity, and high concentrations are required to inhibit cell growth, migration, and invasion. These data support the hypothesis that CAIX activity, shown to be important in regulating extracellular pH, does not underlie its ability to control cell growth.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Anhidrasa Carbónica IX/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/uso terapéutico , Anhidrasa Carbónica II/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Concentración de Iones de Hidrógeno , Modelos Moleculares , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico
4.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33537821

RESUMEN

Endothelial dysfunction and diabetic vascular disease induced by chronic hyperglycemia involve complex interactions among high glucose, long non­coding RNAs (lncRNAs), microRNAs (miRNAs or miRs) and the Ser/Thr kinase AKT. However, the molecular mechanisms underlying the regulatory crosstalk between these have not yet been completely elucidated. Thus, the present study aimed to explore the molecular mechanisms whereby high glucose (HG)­induced lncRNA MIR181A2HG modulates human umbilical vein endothelial cell (HUVEC) proliferation and migration by regulating AKT2 expression. The persistent exposure of HUVECs to HG resulted in MIR181A2HG downregulation and thus reduced its ability to sponge miR­6832­5p, miR­6842­5p and miR­8056, subsequently leading to an increase in miR­6832­5p, miR­6842­5p and miR­8056 levels. Mechanistically, miR­6832­5p, miR­6842­5p and miR­8056 were found to target the 3'UTR of AKT2 mRNA in HUVECs, and the increase in their levels led to a decreased expression of AKT2. Thus, this also led to the suppression of HUVEC proliferation and migration, and the formation of capillary­like structures. Moreover, the suppression of HUVEC proliferation and migration induced by MIR181A2HG downregulation was accompanied by changes in glucose metabolism. On the whole, the present study demonstrates that the downregulation of lncRNA MIR181A2HG by HG impairs HUVEC proliferation and migration by dysregulating the miRNA/AKT2 axis. The MIR181A2HG/miRNA/AKT2 regulatory axis may thus be a potential therapeutic target for HG­induced endothelial dysfunction.


Asunto(s)
Movimiento Celular/efectos de los fármacos , Regulación hacia Abajo/genética , Glucosa/toxicidad , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , MicroARNs/genética , Proteínas Proto-Oncogénicas c-akt/genética , ARN Largo no Codificante/genética , Regiones no Traducidas 3'/genética , Secuencia de Bases , Capilares/efectos de los fármacos , Capilares/crecimiento & desarrollo , Proliferación Celular/efectos de los fármacos , Glucosa/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Modelos Biológicos , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/metabolismo
5.
Chem Biol Interact ; 337: 109366, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33549581

RESUMEN

Tripartite motif-containing protein 26 (TRIM26) is a member of the TRIM protein family and has been demonstrated to play crucial roles in several types of cancers. However, the biological role of TRIM26 in bladder cancer and the mechanism have not been studied. In this study, we investigated the expression of TRIM26 in bladder cancer tissues and their adjacent non-tumor tissues by Western blot and qRT-PCR. In vitro investigations were performed to assess the roles of TRIM26 in bladder cancer using TRIM26-silencing and TRIM26-overexpressing bladder cancer cell lines. MTT and EdU assays were performed to evaluate cell proliferation. Cell migration and invasion were determined by transwell assays. Western blot analysis was performed to detect the expression levels of p-Akt, Akt, p-GSK3ß, GSK3ß, ß-catenin and c-Myc. Our results showed that TRIM26 expression was upregulated in human bladder cancer tissues and cell lines at both mRNA and protein levels. Knockdown of TRIM26 significantly inhibited the proliferation, migration and invasion of bladder cancer cells. In contrast, TRIM26 overexpression promoted bladder cancer cell proliferation, cell migration and invasion. Furthermore, knockdown of TRIM26 significantly decreased the levels of p-Akt, p-GSK3ß, ß-catenin and c-Myc in bladder cancer cells. Additionally, induction of Akt by SC79 treatment reversed the inhibitory effects of TRIM26 knockdown on the cellular behaviors of bladder cancer cells, while inhibition of ß-catenin reversed the effects of TRIM26 overexpression on the behaviors. Finally, knockdown of TRIM26 attenuated the growth of tumor xenografts in nude mice. In conclusion, these findings demonstrated that TRIM26 exerted an oncogenic role in bladder cancer through regulation of cell proliferation, migration and invasion via the Akt/GSK3ß/ß-catenin pathway.


Asunto(s)
Proliferación Celular , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias de la Vejiga Urinaria/patología , beta Catenina/metabolismo , Acetatos/farmacología , Animales , Benzopiranos/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas c-akt/agonistas , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , ARN Interferente Pequeño/uso terapéutico , Transducción de Señal/efectos de los fármacos , Trasplante Heterólogo , Proteínas de Motivos Tripartitos/antagonistas & inhibidores , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo
6.
Int J Nanomedicine ; 16: 1051-1066, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33603368

RESUMEN

Background: This study was aimed to prepare a novel magnetic thermosensitive cationic liposome drug carrier for the codelivery of Oxaliplatin (OXA) and antisense lncRNA of MDC1 (MDC1-AS) to Cervical cancer cells and evaluate the efficiency of this drug carrier and its antitumor effects on Cervical cancer. Methods: Thermosensitive magnetic cationic liposomes were prepared using thin-film hydration method. The OXA and MDC1-AS vectors were loaded into the codelivery system, and the in vitro OXA thermosensitive release activity, efficiency of MDC1-AS regulating MDC1, in vitro cytotoxicity, and in vivo antitumor activity were determined. Results: The codelivery system had desirable targeted delivery efficacy, OXA thermosensitive release, and MDC1-AS regulating MDC1. Codelivery of OXA and MDC1-AS enhanced the inhibition of cervical cancer cell growth in vitro and in vivo, compared with single drug delivery. Conclusion: The novel codelivery of OXA and MDC1-AS magnetic thermosensitive cationic liposome drug carrier can be applied in the combined chemotherapy and gene therapy for cervical cancer.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas de Ciclo Celular/genética , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Fenómenos Magnéticos , Terapia Molecular Dirigida , Oxaliplatino/uso terapéutico , ARN Largo no Codificante/administración & dosificación , Neoplasias del Cuello Uterino/terapia , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Cationes , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Liberación de Fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Liposomas , Ratones Endogámicos BALB C , Ratones Desnudos , Oxaliplatino/farmacología , Tamaño de la Partícula , Electricidad Estática , Temperatura , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patología
7.
Int J Nanomedicine ; 16: 1345-1360, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33633450

RESUMEN

Purpose: Despite the extensive development of antibacterial biomaterials, there are few reports on the effects of materials on the antibacterial ability of the immune system, and in particular of neutrophils. In this study, we observe differences between the in vivo and in vitro anti-infective efficacies of silver nanoparticles (AgNPs). The present study was designed to further explore the mechanism for this inconsistency using ex vivo models and in vitro experiments. Methods: AgNPs were synthesized using the polyol process and characterized by transmission electron microscopy and X-ray photoelectron spectroscopy. The antibacterial ability of AgNPs and neutrophils was tested by the spread-plate method. The infected air pouch model was prepared to detect the antimicrobial ability of AgNPs in vivo. Furthermore, blood-AgNPs-bacteria co-culture model and reactive oxygen species (ROS) measurement were used to evaluate the effect of AgNPs to neutrophil-mediated phagocytosis and ROS production. Results: The antibacterial experiments in vitro showed that AgNPs had superior antibacterial properties in cell compatible concentration. While, AgNPs had no significant antibacterial effect in vivo, and pathological section in AgNPs group indicated less neutrophil infiltration in inflammatory site than S. aureus group. Furthermore, AgNPs were found to reduce the phagocytosis of neutrophils and inhibit their ability to produce ROS and superoxide during ex vivo and in vitro experiments. Conclusion: This study selects AgNPs as the representative of inorganic nano-biomaterials and reveals the phenomenon and the mechanism underlying the significant AgNPs-induced inhibition of the antibacterial ability of neutrophils, and may have a certain enlightening effect on the development of biomaterials in the future. In the fabrication of antibacterial biomaterials, however, attention should be paid to both cell and immune system safety to make the antibacterial properties of the biomaterials and innate immune system complement each other and jointly promote the host's ability to resist the invasion of pathogenic microorganisms.


Asunto(s)
Antibacterianos/farmacología , Sistema Inmunológico/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Nanopartículas del Metal/química , Neutrófilos/citología , Fagocitosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Plata/farmacología , Animales , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Nanopartículas del Metal/ultraestructura , Pruebas de Sensibilidad Microbiana , Neutrófilos/efectos de los fármacos , ARN/metabolismo , Ratas Sprague-Dawley , Staphylococcus aureus/efectos de los fármacos , Superóxidos/metabolismo
8.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33537802

RESUMEN

Paris saponin H (PSH) is a type of steroid saponin derived from Rhizoma Paridis (RP; the rhizome of Paris). In our previous studies, saponins from RP exerted antiglioma activity in vitro. However, the effects of PSH on glioma have not been elucidated. The aim of the present study was to evaluate the effects of PSH on U251 glioblastoma cells and elucidate the possible underlying mechanism. The cells were treated with PSH at various concentrations for 48 h, and the cell viability, invasion, apoptosis and cycle progression were assessed using specific assay kits. The activation of Akt, 44/42­mitogen­activated protein kinase (MAPK) and the expression levels of A1 adenosine receptor (ARA1) and ARA3 were assessed by western blotting. The results demonstrated that PSH inhibited cell viability, migration and invasion, and induced apoptosis. Treatment of U251 cells with PSH induced the upregulation of p21 and p27, and the downregulation cyclin D1 and S­phase kinase associated protein 2 protein expression levels, which induced cell cycle arrest at the G1 phase. The results also demonstrated that PSH inhibited the expression of ARA1, and the agonist of ARA1, 2­chloro­N6­cyclopentyladenosine, reversed the effects of PSH. Hypoxia induced increases in the ARA3, hypoxia­inducible factor­1α (HIF­1α) and vascular endothelial growth factor (VEGF) protein expression levels, which were associated with the activation of the Akt and P44/42 MAPK pathways. Compared with the hypoxia group, PSH inhibited the expression levels of ARA3, HIF­1α and VEGF, as well as the phosphorylation levels of Akt and 44/42 MAPK, and repressed HIF­1α transcriptional activity. Furthermore, the results demonstrated that PSH inhibited the expression of HIF­1α by inhibiting the phosphorylation of Akt and 44/42 MAPK mediated by ARA3. Taken together, these results suggested that PSH reduced U251 cell viability via the inhibition of ARA1 and ARA3 expression, and further inhibited Akt and 44/42 MAPK phosphorylation, induced apoptosis and cell cycle arrest.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Glioma/metabolismo , Glioma/patología , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A3/metabolismo , Saponinas/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fase G1/efectos de los fármacos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
9.
Int J Nanomedicine ; 16: 789-802, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33568906

RESUMEN

Purpose: The aims of this study were to test the feasibility, targeting specificity and anticancer therapeutic efficacy of CendR motif tLyP-1 functionalized at the N-terminal of ferritin for paclitaxel (PTX) delivery. Methods: A tumor homing and penetrating peptide tLyP-1 was fused to the N-terminal of human H chain ferritin (HFtn) to generate a dual-targeting nanoparticle delivery system. PTX molecules were encapsulated into the HFtn nanocage using the disassembly/assembly method by adjusting pHs. Cellular uptake was examined by confocal laser scanning microscopy (CLSM) and flow cytometry. The MTT assay was used to test the cytotoxicity of various PTX-loaded NPs against MDA-MB-231 and SMMC-7721 tumor cells. The wound healing and cell migration assays were conducted to assess the inhibitory effect on cell motility and metastasis. The inhibition effect on the SMMC-7721 tumor spheroids was studied and penetration ability was evaluated by CLSM. The antitumor efficacy of PTX-loaded NPs was assessed in MDA-MB-231 breast cancer xenografted in female BALB/c nude mice. Results: Compared with HFtn-PTX, in vitro studies demonstrated that the tLyP-1-HFtn-PTX displayed enhanced intracellular delivery and better cytotoxicity and anti-invasion ability against both SMMC-7721 and MDA-MB-231 cells. The better penetrability and growth inhibitory effect on SMMC-7721 tumor spheroids were also testified. In vivo distribution and imaging demonstrated that the tLyP-1-HFtn-PTX NPs were selectively accumulated and penetrated at the tumor regions. Verified by the breast cancer cells model in BABL/c nude mice, tLyP-1-HFtn-PTX displayed higher in vivo therapeutic efficacy with lower systemic toxicity. Conclusion: Ferritin decorated with tumor-homing penetration peptide tLyP-1 at the N terminal could deliver PTX specifically inside the cell via receptor-mediated endocytosis with better efficacy. The peptide tLyP-1 which is supposed to work only at the C terminus showed enhanced tumor tissue penetration and antitumor efficacy, demonstrating that it also worked at the N-terminal of HFtn.


Asunto(s)
Apoferritinas/química , Sistemas de Liberación de Medicamentos , Paclitaxel/administración & dosificación , Péptidos Cíclicos/química , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanopartículas/ultraestructura , Paclitaxel/farmacología , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/patología , Cicatrización de Heridas/efectos de los fármacos
10.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540939

RESUMEN

Pulmonary hypertension (PH) is characterized by a progressive elevation of mean arterial pressure followed by right ventricular failure and death. Previous studies have indicated that numerous inhibitors of receptor tyrosine kinase signaling could be either beneficial or detrimental for the treatment of PH. Here we investigated the therapeutic potential of the multi-kinase inhibitor regorafenib (BAY 73-4506) for the treatment of PH. A peptide-based kinase activity assay was performed using the PamStation®12 platform. The 5-bromo-2'-deoxyuridine proliferation and transwell migration assays were utilized in pulmonary arterial smooth muscle cells (PASMCs). Regorafenib was administered to monocrotaline- and hypoxia-induced PH in rats and mice, respectively. Functional parameters were analyzed by hemodynamic and echocardiographic measurements. The kinase activity assay revealed upregulation of twenty-nine kinases in PASMCs from patients with idiopathic PAH (IPAH), of which fifteen were established as potential targets of regorafenib. Regorafenib showed strong anti-proliferative and anti-migratory effects in IPAH-PASMCs compared to the control PASMCs. Both experimental models indicated improved cardiac function and reduced pulmonary vascular remodeling upon regorafenib treatment. In lungs from monocrotaline (MCT) rats, regorafenib reduced the phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2. Overall, our data indicated that regorafenib plays a beneficial role in experimental PH.


Asunto(s)
Hipertensión Pulmonar/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Animales , División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hipertensión Pulmonar/enzimología , Hipertensión Pulmonar/etiología , Hipoxia/complicaciones , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Monocrotalina/toxicidad , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Compuestos de Fenilurea/farmacología , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Arteria Pulmonar/citología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Remodelación Vascular/efectos de los fármacos
11.
Food Chem ; 348: 129111, 2021 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-33516994

RESUMEN

In this study, we report a novel peptide corresponding to the sequence of human ß-casein (named BCCY-1), which was identified in our previous peptidome analysis of human milk and has great immunomodulatory activity. The results revealed that peptide BCCY-1, but not the scrambled version, enhanced monocyte migration without obvious toxicities. This selective effect was mediated via increased production of chemokines by peptide stimulated monocytes. Moreover, BCCY-1 exerted its modulatory effects by activating nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling. The abundances of peptide BCCY-1 and the peptides partially encompassing its fragment were found to be lower in preterm milk than in term milk. Our study may lead to new insights into the immunoregulatory effects of casein-derived peptides and facilitate the discovery of novel peptide-based food and pharmaceutical products.


Asunto(s)
Caseínas/química , Inmunidad Innata/efectos de los fármacos , Péptidos/farmacología , Animales , Caseínas/metabolismo , Línea Celular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Leche Humana/metabolismo , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Péptidos/química
12.
ACS Appl Mater Interfaces ; 13(1): 112-122, 2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33397079

RESUMEN

The gold standard treatment for peripheral nerve injuries (PNIs) is the autologous graft, while it is associated with the shortage of donors and results in major complications. In the present study, we engineer a graphene mesh-supported double-network (DN) hydrogel scaffold, loaded with netrin-1. Natural alginate and gelatin-methacryloyl entangled hydrogel that is synthesized via fast exchange of ions and ultraviolet irradiation provide proper mechanical strength and excellent biocompatibility and can also serve as a reservoir for netrin-1. Meanwhile, the graphene mesh can promote the proliferation of Schwann cells and guide their alignments. This approach allows scaffolds to have an acceptable Young's modulus of 725.8 ± 46.52 kPa, matching with peripheral nerves, as well as a satisfactory electrical conductivity of 6.8 ± 0.85 S/m. In addition, netrin-1 plays a dual role in directing axon pathfinding and neuronal migration that optimizes the tube formation ability at a concentration of 100 ng/mL. This netrin-1-loaded graphene mesh tube/DN hydrogel nerve scaffold can significantly promote the regeneration of peripheral nerves and the restoration of denervated muscle, which is even superior to autologous grafts. Our findings may provide an effective therapeutic strategy for PNI patients that can replace the scarce autologous graft.


Asunto(s)
Grafito/química , Hidrogeles/química , Regeneración Nerviosa/efectos de los fármacos , Netrina-1/uso terapéutico , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Nervio Ciático/efectos de los fármacos , Alginatos/química , Alginatos/toxicidad , Animales , Movimiento Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Módulo de Elasticidad , Gelatina/química , Gelatina/toxicidad , Grafito/toxicidad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Hidrogeles/toxicidad , Masculino , Metacrilatos/química , Metacrilatos/toxicidad , Neovascularización Fisiológica/efectos de los fármacos , Ratas Sprague-Dawley , Células de Schwann/efectos de los fármacos , Nervio Ciático/lesiones , Andamios del Tejido/química
13.
Life Sci ; 270: 119112, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33508300

RESUMEN

AIMS: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis. MATERIALS AND METHODS: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo. KEY FINDINGS: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo. SIGNIFICANCE: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.


Asunto(s)
Glioblastoma/metabolismo , Harmina/farmacología , Animales , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , China , Quinasa 1 de Adhesión Focal/metabolismo , Glioblastoma/tratamiento farmacológico , Harmina/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
14.
Cell Prolif ; 54(3): e12997, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33511708

RESUMEN

OBJECTIVES: Stromal cell-derived factor-1 (SDF-1) actively directs endogenous cell homing. Exendin-4 (EX-4) promotes stem cell osteogenic differentiation. Studies revealed that EX-4 strengthened SDF-1-mediated stem cell migration. However, the effects of SDF-1 and EX-4 on periodontal ligament stem cells (PDLSCs) and bone regeneration have not been investigated. In this study, we aimed to evaluate the effects of SDF-1/EX-4 cotherapy on PDLSCs in vitro and periodontal bone regeneration in vivo. METHODS: Cell-counting kit-8 (CCK8), transwell assay, qRT-PCR and western blot were used to determine the effects and mechanism of SDF-1/EX-4 cotherapy on PDLSCs in vitro. A rat periodontal bone defect model was developed to evaluate the effects of topical application of SDF-1 and systemic injection of EX-4 on endogenous cell recruitment, osteoclastogenesis and bone regeneration in vivo. RESULTS: SDF-1/EX-4 cotherapy had additive effects on PDLSC proliferation, migration, alkaline phosphatase (ALP) activity, mineral deposition and osteogenesis-related gene expression compared to SDF-1 or EX-4 in vitro. Pretreatment with ERK inhibitor U0126 blocked SDF-1/EX-4 cotherapy induced ERK signal activation and PDLSC proliferation. SDF-1/EX-4 cotherapy significantly promoted new bone formation, recruited more CXCR4+ cells and CD90+ /CD34- stromal cells to the defects, enhanced early-stage osteoclastogenesis and osteogenesis-related markers expression in regenerated bone compared to control, SDF-1 or EX-4 in vivo. CONCLUSIONS: SDF-1/EX-4 cotherapy synergistically regulated PDLSC activities, promoted periodontal bone formation, thereby providing a new strategy for periodontal bone regeneration.


Asunto(s)
Regeneración Ósea/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Quimiocina CXCL12/metabolismo , Exenatida/farmacología , Ligamento Periodontal/citología , Células del Estroma/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Exenatida/metabolismo , Humanos , Osteogénesis/efectos de los fármacos , Osteogénesis/fisiología , Transducción de Señal/efectos de los fármacos , Células Madre/citología , Células Madre/efectos de los fármacos , Células del Estroma/metabolismo
15.
Anticancer Res ; 41(2): 671-678, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33517271

RESUMEN

BACKGROUND/AIM: Hepatocyte growth factor (HGF) acts as a key regulator in promoting ovarian cancer metastasis. Previously, we observed that YYB-101, a humanized anti-HGF antibody, effectively inhibits ovarian cancer cell migration, invasion, and progression. Here, we evaluated the signaling mechanisms affected by YYB-101 that are important in ovarian cancer cell progression. MATERIALS AND METHODS: Using cell migration, invasion and proliferation assays, we evaluated the effects of YYB-101 on A2780/luc and SKOV3 cells. The effects of YYB-101 on signaling molecules were determined by immunocytochemistry and immunoblot analysis. RESULTS: YYB-101 inhibited HGF-induced ovarian cancer cell motility by down-regulating paxillin phosphorylation and actin-cytoskeleton rearrangement. Also, YYB-101 inhibited ovarian cancer cell proliferation by reducing c-MET phosphorylation and activating apoptosis in vitro and in vivo. These effects were significantly enhanced by combining YYB-101 treatment with paclitaxel, a standard chemotherapy drug. CONCLUSION: YYB-101 can be examined as a new therapeutic agent for the treatment of patients with ovarian cancer.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Antineoplásicos Inmunológicos/farmacología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factor de Crecimiento de Hepatocito/antagonistas & inhibidores , Neoplasias Ováricas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Citoesqueleto/efectos de los fármacos , Citoesqueleto/metabolismo , Citoesqueleto/patología , Femenino , Factor de Crecimiento de Hepatocito/metabolismo , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Proteínas Proto-Oncogénicas c-met/metabolismo , Transducción de Señal , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Mol Carcinog ; 60(2): 151-163, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33428809

RESUMEN

Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34- /PAS+ ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.


Asunto(s)
Carcinoma Hepatocelular/prevención & control , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteína 1 Inhibidora de la Diferenciación/antagonistas & inhibidores , Neoplasias Hepáticas/prevención & control , Neovascularización Patológica/prevención & control , Compuestos de Fenilurea/farmacología , Piridinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Carcinoma Hepatocelular/irrigación sanguínea , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Proteína 1 Inhibidora de la Diferenciación/genética , Proteína 1 Inhibidora de la Diferenciación/metabolismo , Neoplasias Hepáticas/irrigación sanguínea , Neoplasias Hepáticas/genética , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neovascularización Patológica/genética , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética
17.
Chem Biol Interact ; 335: 109367, 2021 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-33412154

RESUMEN

Metastasis is the leading cause of death in retinoblastoma (Rb) patients. Tubeimoside II (TBMS II) is a compound enriched in the Traditional Chinese Medicine (TCM) Tu Bei Mu. It has been shown to induce cytotoxicity of several types of tumors; however, littler is known about its effect on Rb. This study investigated the influence of TBMS II on TGF-ß1-induced metastasis of human retinoblastoma Y-79 and WERI-Rb-1 cells. The data showed that TBMS II significantly inhibited epithelial-mesenchymal transition (EMT), cell adhesion, migration and invasion via reducing TGF-ß1-induced oxidative stress in Rb cells. Further findings revealed that TBMS II exerted its inhibitory effect against TGF-ß1-induced metastatic progression of Rb cells via suppressing redoxosome-dependent EGFR activation including EGFR phosphorylation and oxidation, and the activation of such signaling attenuated TBMS II's effect. Our study reveals that TBMS II impacts on TGF-ß1-induced metastatic progression of Rb cells, and this information may contribute to better understanding the therapeutic potentials of TBMS II on metastatic Rb.


Asunto(s)
Antineoplásicos/farmacología , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Saponinas/farmacología , Triterpenos/farmacología , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
18.
Ecotoxicol Environ Saf ; 210: 111872, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33388592

RESUMEN

BACKGROUND: Epidemiological studies have revealed that sulfur dioxides (SO2) can increase the risk of pregnancy complications such as missed abortion in the first trimester, stillbirth, preterm birth, small for gestational age, gestational diabetes mellitus and preeclampsia, but the mechanisms underlying these findings remains unknown. What is known, however, is that trophoblasts, a type of fetal cell exerting vital immunologic functions to maintain a successful pregnancy, are usually involved in the pathogenic mechanism of pregnancy complications. OBJECTIVE: To study the effect of SO2 derivatives (bisulfite and sulfite, 1:3 M/M) on the function of trophoblasts. METHODS: Swan.71 trophoblast cells were treated with various concentrations of SO2 derivatives to determine the effect of SO2 derivatives on cellular viability by CKK8. Flow cytometry was performed to analyze the effect of SO2 derivatives on apoptosis, cell cycle and intracellular ROS. Wound healing assay and transwell assay were conducted to examine the migration and invasion of Swan.71 cells. Inflammation-related cytokines in the supernatant (IL-1ß, IL-6, IL-8, IL-10 and TNF-α) were measured by IMMULITE®1000 Systems (SIEMENS). The expression level of NLRP3, Caspase1, MMP9, MMP2, STAT3, and p-STAT3 were evaluated by Western Blotting. RESULTS: Exposure to SO2 derivatives significantly decreased cellular viability, arrested cell cycle at S/G2/M phase and induced cell apoptosis of Swan.71 trophoblasts. In addition, the migration and invasion of Swan.71 cell were significantly inhibited. SO2 derivatives also significantly increased IL-1ß secretion while it is NLRP3/Caspase1 independent. IL-6 secretion was significant inhibited accompanied by decreased STAT3 phosphorylation and expression of MMP2 and MMP9. The intracellular ROS level was significantly suppressed by SO2 derivatives. CONCLUSION: SO2 derivatives exert toxic effects on trophoblasts which results in: suppressing cellular viability and intracellular ROS level, interfering with cell proliferation through arresting cell cycle, inducing cell apoptosis, disturbing inflammation-related cytokines secretion and inhibiting motility. Decreased ROS/IL-6/STAT3 levels play a role in inhibited cell viability, cell cycle arrest, apoptosis and defective motility.


Asunto(s)
Sulfitos/toxicidad , Trofoblastos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Femenino , Humanos , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Embarazo , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción STAT3/metabolismo , Trofoblastos/metabolismo
19.
Int J Nanomedicine ; 16: 457-467, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33488080

RESUMEN

Background: Tumor angiogenesis plays a crucial role in tumor development, and recent efforts have been focused on combining proapoptotic and antiangiogenic activities to enhance antitumor therapy. Methods: In this study, galactose-modified liposomes (Gal-LPs) were prepared for co-delivery of doxorubicin (DOX) and combretastatin A4 phosphate (CA4P). The co-cultured system composed of BEL-7402 and human umbilical vein endothelial cells (HUVEC) cells was established to effectively evaluate in vitro anti-tumor activity through cell viability and cell migration assay. Furthermore, both in vivo bio-distribution and anti-hepatoma effect of DOX&CA4P/Gal-LPs were investigated on H22 tumor cell-bearing mice. Results: The results showed that DOX&CA4P/Gal-LPs were spherical with a mean particle size of 143 nm, and could readily be taken up by BEL-7402 cells. Compared with a mixture of free DOX and CA4P, the DOX&CA4P/Gal-LPs were more effective in inhibiting cell migration and exhibited stronger cytotoxicity against BEL-7402 cells alone or a co-cultured system. The in vitro studies showed that the co-cultured system was a more effective model to evaluate the anti-tumor activity of combination therapy. Moreover, DOX&CA4P/Gal-LPs exhibited a greater anti-hepatoma effect than other drug formulations, indicating that Gal-LPs could promote drug accumulation in the tumor region and improve the anti-tumor activity. Conclusion: Gal-LPs co-loaded with chemotherapeutic and antiangiogenic drugs are a promising strategy for anti-hepatoma therapy.


Asunto(s)
Doxorrubicina/química , Galactosa/química , Liposomas/química , Estilbenos/química , Animales , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Composición de Medicamentos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Neoplasias Hepáticas/patología , Ratones , Tamaño de la Partícula , Estilbenos/farmacología
20.
Aquat Toxicol ; 231: 105740, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33440272

RESUMEN

Ensuring that oocytes are fertilized by a single sperm during broadcast spawning is crucial for the fertilization success of many marine invertebrates. Although the adverse impacts of ocean acidification (OA) on various marine species have been revealed in recent years, its impact on polyspermy and the underlying mechanisms involved remain largely unknown. Therefore, in the present study, the effect of OA on polyspermy risk was assessed in a broadcast spawning bivalve, Tegillarca granosa. In addition, the impacts of OA on the two polyspermy blocking processes, the fast block (membrane depolarization) and the permanent block (cortical reaction), were investigated. The results show that the exposure of oocytes to two future OA scenarios (pH 7.8 and pH 7.4) leads to significant increases in polyspermy risk, about 1.70 and 2.38 times higher than the control, respectively. The maximum change in the membrane potential during oocyte membrane depolarization markedly decreased to 15.79 % (pH 7.8) and 34.06 % (pH 7.4) of the control value. Moreover, the duration of oocyte membrane depolarization was significantly reduced to approximately 63.38 % (pH 7.8) and 21.91 % (pH 7.4) of the control. In addition, cortical granule exocytosis, as well as microfilament migration, were significantly arrested by OA treatment. Exposure to future OA scenarios also led to significant reductions in the ATP and Ca2+ content of the oocytes, which may explain the hampered polyspermy blocking. Overall, the present study suggests that OA may significantly increase polyspermy risk in T. granosa by inhibiting membrane depolarization and arresting cortical granule exocytosis.


Asunto(s)
Ácidos/química , Bivalvos/fisiología , Gránulos Citoplasmáticos/metabolismo , Exocitosis , Potenciales de la Membrana/fisiología , Océanos y Mares , Espermatozoides/fisiología , Citoesqueleto de Actina/efectos de los fármacos , Citoesqueleto de Actina/metabolismo , Adenosina Trifosfato/farmacología , Animales , Calcio/metabolismo , Movimiento Celular/efectos de los fármacos , Gránulos Citoplasmáticos/efectos de los fármacos , Exocitosis/efectos de los fármacos , Femenino , Fertilización/efectos de los fármacos , Concentración de Iones de Hidrógeno , Masculino , Potenciales de la Membrana/efectos de los fármacos , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Contaminantes Químicos del Agua/toxicidad
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