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1.
Biomed Environ Sci ; 34(1): 40-49, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33531106

RESUMEN

Objective: Epidemiological studies reveal that exposure to fine particulate matter (aerodynamic diameter ≤ 2.5 µm, PM 2.5) increases the morbidity and mortality of respiratory diseases. Emerging evidence suggests that human circulating extracellular vesicles (EVs) may offer protective effects against injury caused by particulate matter. Currently, however, whether EVs attenuate PM 2.5-induced A549 cell apoptosis is unknown. Methods: EVs were isolated from the serum of healthy subjects, quantified via nanoparticle tracking analysis, and qualified by the marker protein CD63. PM 2.5-exposed (50 µg/mL) A549 cells were pre-treated with 10 µg/mL EVs for 24 h. Cell viability, cell apoptosis, and AKT activation were assessed via Cell Counting Kit-8, flow cytometry, and Western blot, respectively. A rescue experiment was also performed using MK2206, an AKT inhibitor. Results: PM 2.5 exposure caused a 100% increase in cell apoptosis. EVs treatment reduced cell apoptosis by 10%, promoted cell survival, and inhibited the PM 2.5-induced upregulation of Bax/Bcl2 and cleaved caspase 3/caspase 3 in PM 2.5-exposed A549 cells. Moreover, EVs treatment reversed PM 2.5-induced reductions in p-AKT Thr308 and p-AKT Ser473. AKT inhibition attenuated the anti-apoptotic effect of EVs treatment on PM 2.5-exposed A549 cells. Conclusions: EVs treatment promotes cell survival and attenuates PM 2.5-induced cell apoptosis via AKT phosphorylation. Human serum-derived EVs may be an efficacious novel therapeutic strategy in PM 2.5-induced lung injury.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Vesículas Extracelulares , Material Particulado/toxicidad , Sustancias Protectoras/farmacología , Suero , Células A549 , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-akt/metabolismo
2.
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
3.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33537813

RESUMEN

The activation of oxidative stress is a primary cause of chondrocyte apoptosis in osteoarthritis (OA). The 78­kDa glucose­regulated protein (GRP78)/mammalian target of rapamycin (mTOR) signaling pathway has been demonstrated to be linked with the endoplasmic reticulum (ER) and autophagy. Hydrogen sulfide (H2S) has been reported to exert antioxidant effects. The present study investigated oxidative stress levels via 2',7'­dichlorofluorescin diacetate and MitoSOX staining, apoptosis rates via flow cytometry and the expression levels of ER stress­related proteins in GYY4137 (donor of H2S)­treated chondrocytes (CHs). CHs were isolated from the bilateral hip joints of male rats to examine mitochondrial permeability transition pore opening­ and mTOR signaling pathway­related proteins. The results demonstrated that tert­Butyl hydroperoxide (TBHP) increased CH apoptosis, and treatment with GYY4137 ameliorated TBHP­mediated the generation of ROS and CH apoptosis. Moreover, TBHP­treated CHs displayed elevated ER stress sensor expression levels and apoptotic rates; however, the TBHP­induced protein expression levels were decreased following GYY4137 treatment. In the present study, treatment with either GYY4137 or transfection with GRP78 siRNA both suppressed the activation of p­P70S6k and p­mTOR. H2S played an important role in regulating ER stress in TBHP­stimulated CHs. GYY4137 promoted autophagy, which was accompanied by the inhibition of ER stress. On the whole, the present study demonstrates that TBHP­induced oxidative stress stimulates ER interactions and CH apoptosis, which are suppressed by exogenous H2S via modulating the GRP78/mTOR signaling pathway.


Asunto(s)
Condrocitos/metabolismo , Condrocitos/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas de Choque Térmico/metabolismo , Sulfuro de Hidrógeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cloroquina/farmacología , Condrocitos/efectos de los fármacos , Citoprotección/efectos de los fármacos , Masculino , Morfolinas/química , Morfolinas/farmacología , Compuestos Organotiofosforados/química , Compuestos Organotiofosforados/farmacología , Peróxidos/farmacología , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
4.
Nat Commun ; 12(1): 723, 2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33526787

RESUMEN

Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.


Asunto(s)
Adenocarcinoma/secundario , Neoplasias Óseas/secundario , Células Madre Mesenquimatosas/patología , Neoplasias de la Próstata/patología , Receptores de Interferón/metabolismo , Ácidos Aminosalicílicos/farmacología , Ácidos Aminosalicílicos/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Bencenosulfonatos/farmacología , Bencenosulfonatos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Medios de Cultivo Condicionados/metabolismo , Modelos Animales de Enfermedad , Docetaxel/farmacología , Docetaxel/uso terapéutico , Humanos , Interferones/genética , Interferones/metabolismo , Masculino , Ratones Noqueados , Osteoblastos/patología , Cultivo Primario de Células , Neoplasias de la Próstata/tratamiento farmacológico , ARN Interferente Pequeño/metabolismo , Receptores de Interferón/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Tibia/patología
5.
Int J Nanomedicine ; 16: 579-589, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33531802

RESUMEN

Purpose: Breast cancer is one of the most lethal types of cancer in women. Curcumin showed therapeutic potential against breast cancer, but applying that by itself does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. Moreover, poor water solubility of curcumin causes accumulation of a high concentration of curcumin and so decrease its permeability to the cell. Many strategies are employed to reduce curcumin metabolism such as adjuvants and designing novel delivery systems. Therefore, in this study sodium alginate and chitosan were used to synthesize the hydrogels that are known as biocompatible, hydrophilic and low toxic drug delivery systems. Also, folic acid was used to link to chitosan in order to actively targetfolate receptors on the cells. Methods: Chitosan-ß-cyclodextrin-TPP-Folic acid/alginate nanoparticles were synthesized and then curcumin was loaded on them. Interaction between the constituents of the particles was characterized by FTIR spectroscopy. Morphological structures of samples were studied by FE-SEM. Release profile of curcumin was determined by dialysis membrane. The cytotoxic test was done on the Kerman male breast cancer (KMBC-10) cell line by using MTT assay. The viability of cells was detected by fluorescent staining. Gene expression was investigated by real-time PCR. Results: The encapsulation of curcumin into nano-particles showed an almost spherical shape and an average particle size of 155 nm. In vitro cytotoxicity investigation was indicated as dose-respond reaction against cancer breast cells after 24 h incubation. On the other hand, in vitro cell uptake study revealed active targeting of CUR-NPs into spheroids. Besides, CXCR 4 expression was detected about 30-fold less than curcumin alone. The CUR-NPs inhibited proliferation and increased apoptosis in spheroid human breast cancer cells. Conclusion: Our results showed the potential of NPs as an effective candidate for curcumin delivery to the target tumor spheroids that confirmed the creatable role of folate receptors.


Asunto(s)
Alginatos/química , Quitosano/química , Curcumina/farmacología , Nanosferas/química , Esferoides Celulares/patología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Fluorescencia , Ácido Fólico/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Masculino , Nanosferas/ultraestructura , Tamaño de la Partícula , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Esferoides Celulares/efectos de los fármacos
6.
Med Sci Monit ; 27: e926492, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33563887

RESUMEN

BACKGROUND The aim of this study was to evaluate the potential role of dual oxidase 1 (DUOX1) in wound healing. MATERIAL AND METHODS Primary fibroblasts were isolated from wound granulation tissue. Fibroblasts cell lines were established using DUOX1 overexpression and interference. Cell proliferation and reactive oxygen species (ROS) production were measured and compared among the groups. RESULTS DUOX1 expression was highest in the slow-healing tissues (P<0.05). Knockdown of DUOX1 significantly increased cell proliferation and inhibited ROS production and cell apoptosis (P<0.01). Moreover, expression of malondialdehyde (MDA) was significantly reduced, while expression of superoxide dismutase (SOD) expression was significantly increased (P<0.01). In addition, DUOX1 silencing significantly upregulated collagen I, collagen III, and NF-kappaB protein levels in the cytoplasm, and inhibited the protein levels of P21, P16, and NF-kappaB in the nucleus (P<0.01). Overexpression of DUOX1 caused a reverse reaction mediated by knockdown of DUOX1. When DUOX1-overexpressing cells were treated with the ROS inhibitor N-acetyl-L-cysteine (NAC), the protein levels that were increased by DUOX1 overexpression were reversed. CONCLUSIONS These results suggest that knockdown of DUOX1 significantly benefits wound healing, likely by the regulation of oxidative stress via NF-kappaB pathway activation.


Asunto(s)
Oxidasas Duales/metabolismo , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cicatrización de Heridas/fisiología , Acetilcisteína/farmacología , Adulto , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Células Cultivadas , Oxidasas Duales/genética , Femenino , Fibroblastos , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Cultivo Primario de Células , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Superóxido Dismutasa/metabolismo , Cicatrización de Heridas/efectos de los fármacos
7.
Nat Commun ; 12(1): 1022, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589584

RESUMEN

Development of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid-liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Mieloma Múltiple/tratamiento farmacológico , Coactivador 3 de Receptor Nuclear/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Bortezomib/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 4 , Resistencia a Antineoplásicos/genética , Femenino , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Coactivador 3 de Receptor Nuclear/antagonistas & inhibidores , Coactivador 3 de Receptor Nuclear/metabolismo , Inhibidores de Proteasoma/farmacología , Recurrencia , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , Translocación Genética , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Ecotoxicol Environ Saf ; 208: 111608, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396128

RESUMEN

Lead (Pb) is one of the most toxic heavy metal environmental pollutants due to its widespread use of the industry and it is a harmful substance for human and animal health. This study was conducted to investigate the potential protective effects of ellagic acid (EA) on performance, egg quality, antioxidant parameters, and apoptotic pathway proteins in laying quails exposed to Pb toxicity. A total of 168 (15-week old) laying quails (Coturnix coturnix Japonica) were divided into 6 experimental groups (with similar initial average body weight). Birds were fed 1 of 6 diets for 8 weeks: 1 - Control (basal diet), 2 - Pb (basal diet + 100 mg/kg Pb), 3 - EA-300 (basal diet + 300 mg/kg EA), 4 - EA-500 (basal diet + 500 mg/kg EA), 5 - Pb + EA-300 (basal diet + 100 mg/kg Pb + 300 mg/kg EA), 6 - Pb + EA-500 (basal diet + 100 mg/kg Pb + 500 mg/kg EA). The results showed that adding 100 mg/kg of Pb to basal diet was adversely affected the performance parameters and, feed intake and egg production were significantly decreased by Pb supplementation (P < 0.01). However, the EA supplementation to Pb groups improved the performance parameters. Compared with the Pb alone group, in Pb + EA-500 group increased egg production by 8.4%. There were no significant differences in the Haugh unit, albumen index, and yolk index among groups (P > 0.05). Liver and kidney tissues of Pb group malondialdehyde (MDA) level increased (P < 0.001) and, GSH, GSH-Px, and CAT values decreased (P < 0.001) but, EA supplementation alleviated this condition (P < 0.001). The protein levels of caspase-3 and -9 were significantly increased in the Pb group compared to the control group, whereas EA supplementation alleviated the Pb-induced apoptosis by decreasing caspase-3 and -9 levels in the liver tissue (p < 0.001). In laying quails exposed to Pb toxicity, EA supplementation improves the performance parameters, enhances the antioxidant defense system, and suppresses apoptosis via regulates the expression of caspase-3 and -9. Thus, it was concluded that EA (especially 500 mg/kg) can ameliorate the toxic effects of Pb exposure in quails.


Asunto(s)
Apoptosis/efectos de los fármacos , Coturnix/metabolismo , Ácido Elágico/farmacología , Plomo/toxicidad , Óvulo/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Alimentación Animal , Animales , Antioxidantes/metabolismo , Peso Corporal/efectos de los fármacos , Coturnix/crecimiento & desarrollo , Suplementos Dietéticos , Ácido Elágico/metabolismo , Femenino , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Malondialdehído/metabolismo , Óvulo/metabolismo
9.
Ecotoxicol Environ Saf ; 208: 111696, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396027

RESUMEN

With the widespread application and inevitable environmental exposure, silver nanoparticles (AgNPs) can be accumulated in various organs. More serious concerns are raised on the biological safety and potential toxicity of AgNPs in the central nervous system (CNS), especially in the hippocampus. This study aimed to investigate the biological effects and the role of PI3K/AKT/mTOR signaling pathway in AgNPs mediated cytotoxicity using the mouse hippocampal neuronal cell line (HT22 cells). AgNPs reduced cell viability and induced membrane leakage in a dose-dependent manner, determined by the MTT and LDH assay. In doses of 25, 50, 100 µg mL-1 for 24 h, AgNPs promoted the excessive production of reactive oxygen species (ROS) and caused the oxidative stress in HT22 cells. AgNPs induced autophagy, determined by the transmission electron microscopy observation, upregulation of LC3 II/I and downregulation of p62 expression levels. The mechanistic investigation showed that the PI3K/AKT/mTOR signaling pathway was activated by phosphorylation, which was enrolled in an AgNP-induced autophagy process. AgNPs could further trigger the apoptosis by upregulation of caspase-3 and Bax and downregulation of Bcl-2 in HT22 cells. These results revealed AgNP-induced cytotoxicity in HT22 cells, which was mediated by autophagy and apoptosis via the PI3K/AKT/mTOR signaling pathway. The study could provide the experimental evidence and explanation for the potential neurotoxicity triggered by AgNPs in vitro.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Transducción de Señal/efectos de los fármacos , Plata/toxicidad , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
10.
Ecotoxicol Environ Saf ; 208: 111702, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396033

RESUMEN

Cellular models exhibiting human physiological features of pseudostratified columnar epithelia, provide a more realistic approach for elucidating detailed mechanisms underlying PM2.5-induced pulmonary toxicity. In this study, we characterized the barrier and mucociliary functions of differentiated human small airway epithelial cells (SAECs), cultured at the air-liquid interface (ALI). Due to the presence of mucociliary protection, particle internalization was reduced, with a concomitant decrease in cytotoxicity in differentiated S-ALI cells, as compared to conventional submerged SAEC cultures. After 24-hour exposure to PM2.5 surrogates, 117 up-regulated genes and 156 down-regulated genes were detected in S-ALI cells, through transcriptomic analysis using the Affymetrix Clariom™ S Human Array. Transcription-level changes in >60 signaling pathways, were revealed by functional annotation of the 273 differentially expressed genes, using the PANTHER Gene List Analysis. These pathways are involved in multiple cellular processes, that include inflammation and apoptosis. Exposure to urban PM2.5 led to complex responses in airway epithelia, including a net induction of downstream pro-inflammatory and pro-apoptotic responses. Collectively, this study highlights the importance of using the more advanced ALI model rather than the undifferentiated submerged model, to avoid over-assessment of inhaled particle toxicity in human. The results of our study also suggest that reduction of ambient PM2.5 concentrations would have a protective effect on respiratory health in humans.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Células Epiteliales/efectos de los fármacos , Material Particulado/toxicidad , Transcriptoma/efectos de los fármacos , Contaminantes Atmosféricos/química , Apoptosis/efectos de los fármacos , Células Cultivadas , Células Epiteliales/metabolismo , Células Epiteliales/patología , Perfilación de la Expresión Génica , Humanos , Tamaño de la Partícula , Material Particulado/química , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
11.
Ecotoxicol Environ Saf ; 208: 111613, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396133

RESUMEN

The environmental effects of additives have attracted increasing attention. Sodium dehydroacetate (DHA-S), as an approved preservative, is widely added in processed foods, cosmetics and personal care products. However, DHA-S has been recently reported to induce hemorrhage and coagulation aberration in rats. Yet little is known about the ecotoxicological effect and underlying mechanisms of DHA-S. Here, we utilized the advantage of zebrafish model to evaluate such effects. DHA-S induced cerebral hemorrhage, mandibular dysplasia and pericardial edema in zebrafish after 24 h exposure (48-72 hpf) at 50 mg/L. We also observed the defective heart looping and apoptosis in DHA-S-treated zebrafish through o-dianisidine and acridine orange staining. Meanwhile, DHA-S induced the deficiency of Ca2+ and vitamin D3 in zebrafish. We further demonstrated that DHA-S stimulated Ca2+ influx resulting in Ca2+-dependent mitochondrial damage in cardiomyocytes. Additionally, DHA-S inhibited glucose uptake and repressed the biosynthesis of amino acids. Finally, we identified that sodium bicarbonate could rescue zebrafish from DHA-S induced cardiovascular toxicity. Altogether, our results suggest that DHA-S is a potential risk for cardiovascular system.


Asunto(s)
Calcio/metabolismo , Embrión no Mamífero/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Corazón/efectos de los fármacos , Pironas/toxicidad , Pez Cebra , Animales , Apoptosis/efectos de los fármacos , Cardiotoxicidad , Línea Celular , Hemorragia Cerebral/inducido químicamente , Relación Dosis-Respuesta a Droga , Edema Cardíaco/inducido químicamente , Corazón/embriología , Miocardio/metabolismo , Miocardio/patología , Pericardio/efectos de los fármacos , Pericardio/patología , Ratas , Pez Cebra/crecimiento & desarrollo
12.
Ecotoxicol Environ Saf ; 208: 111614, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396134

RESUMEN

A novel gill cell line from pearl gentian grouper (Epinephelus lanceolatus♂×Epinephelus fuscoguttatus♀, PGGG cell line) was established, its application in cadmium (Cd) toxicology was demonstrated in this study. Primary cultures and PGGG subcultures were carried out at 25 °C in Dulbecco's Modified Eagle medium/F12 medium (1:1; pH 7.2) supplemented with 15% fetal bovine serum (FBS). Primary PGGG cells were spindle-shaped, proliferated into a confluent monolayer within two weeks and were continuously subcultured over passage 60. The growth of cells at passages 20, 40, and 60 was examined. Chromosome analysis revealed that the chromosomal number of normal PGGG cells was 48, but the number of cells with the normal chromosomes number decreased during the passaging process. Cadmium is one of the most toxic metals in aquatic systems and has been associated with multiple animal and human health problems. To interpret the cytotoxicity and related mechanisms of cadmium, PGGG cells were used as an in vitro model. After treatment with cadmium at concentrations ranging from 1 µM to 500 µM, PGGG cells demonstrated dose- and time-dependent cytotoxicity, manifested as morphological abnormalities and a viability decline. Further, it was found that the reactive oxygen species (ROS) and malondialdehyde (MDA) levels were elevated following cadmium exposure, and related genes involved in the antioxidant system, including those encoding catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and Kelch-like- ECH-associated protein 1 (Keap1), were regulated differently. In addition, PGGG cells treated with cadmium had the typical features associated with apoptosis, including phosphatidylserine (PS) externalization; upregulated expression of caspase-3, -8, and -9; and apoptotic body formation. In general, the PGGG cell line may serve as a useful tool for studying the toxic mechanisms of cadmium or other toxicants or for toxicity testing and environment monitoring.


Asunto(s)
Apoptosis/efectos de los fármacos , Lubina , Cadmio/toxicidad , Expresión Génica/efectos de los fármacos , Branquias , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Contaminantes Químicos del Agua/toxicidad , Animales , Antioxidantes/metabolismo , Catalasa/genética , Catalasa/metabolismo , Técnicas de Cultivo de Célula , Línea Celular , Supervivencia Celular/efectos de los fármacos , Branquias/citología , Proteína 1 Asociada A ECH Tipo Kelch/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo
13.
Ecotoxicol Environ Saf ; 208: 111752, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396077

RESUMEN

Arsenic is a toxic heavy metal vastly dispersed all over the earth crust. It manifests several major adverse health issues to millions of arsenic exposed populations. Arsenic is associated with different types of cancer, cardiovascular disorders, diabetes, hypertension and many other diseases. On the contrary, arsenic (arsenic trioxide, As2O3) is used as a chemotherapeutic agent in the treatment of acute promyelocytic leukemia. Balance between arsenic induced cellular proliferations and apoptosis finally decide the outcome of its transformation rate. Arsenic propagates signals via cellular and nuclear pathways depending upon the chemical nature, and metabolic-fates of the arsenical compounds. Arsenic toxicity is propagated via ROS induced stress to DNA-repair mechanism and mitochondrial stability in the cell. ROS induced alteration in p53 regulation and some mitogen/ oncogenic functions determine the transformation outcome influencing cyclin-cdk complexes. Growth factor regulator proteins such as c-Jun, c-fos and c-myc are influenced by chronic arsenic exposure. In this review we have delineated arsenic induced ROS regulations of epidermal growth factor receptor (EGFR), NF-ĸß, MAP kinase, matrix-metalloproteinases (MMPs). The role of these signaling molecules has been discussed in relation to cellular apoptosis, cellular proliferation and neoplastic transformation. The arsenic stimulated pathways which help in proliferation and neoplastic transformation ultimately resulted in cancer manifestation whereas apoptotic pathways inhibited carcinogenesis. Therapeutic strategies against arsenic should be designed taking into account all these factors.


Asunto(s)
Arsénico/fisiología , Proliferación Celular/fisiología , Plásticos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arsénico/metabolismo , Trióxido de Arsénico/metabolismo , Trióxido de Arsénico/farmacología , Arsenicales/metabolismo , Proliferación Celular/efectos de los fármacos , Humanos , Mitocondrias/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neoplasias , Óxidos/toxicidad , Transducción de Señal/efectos de los fármacos
14.
Ecotoxicol Environ Saf ; 208: 111543, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396091

RESUMEN

Acrylamide (ACR) is generated during thermal processing of carbohydrate-rich foods at high temperature and can directly enter the body through ingestion, inhalation and skin contact. The toxicity of ACR has been widely studied. The main results of these studies show that exposure to ACR can cause neurotoxicity in both animals and humans, and show reproductive toxicity and carcinogenicity in rodent animal models. However, the mechanism of toxicity of ACR has not been studied by metabolomics approaches, and the effect of ACR on autophagy remains unknown. Here, U2OS cell were treated with ACR 6 and 24 h and collected for further study. We have demonstrated that ACR inhibited autophagic flux, and increased ROS content. Accumulation of ROS resulted in increase of apoptosis rates and secretion of inflammatory factors. In addition, significant differences in metabolic profiles were observed between ACR treated and control cells according to multiple analysis models. A total of 73 key differential metabolites were identified. They were involved in multiple metabolic pathways. Among them, exposure to ACR caused glycolysis/gluconeogenesis attenuation by decreasing levels of glycolytic intermediates, reduced the rate of the TCA cycle, while elevating levels of several amino acid metabolites and lipid metabolites. In summary, our study provides useful evidence of cytotoxicity caused by ACR via metabolomics and multiple bioanalytic methods.


Asunto(s)
Acrilamida/toxicidad , Sustancias Peligrosas/toxicidad , Metaboloma , Metabolómica , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos
15.
Ecotoxicol Environ Saf ; 208: 111579, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396102

RESUMEN

Studies about radiation damage in vivo are very significant for healthy risk assessment as well as cancer radiotherapy. Ceramide as a second messenger has been found to be related to radiation-induced apoptosis. However, the detailed mechanisms in living systems are still not fully understood. In the present study, the effects of ceramide in gamma radiation-induced response were investigated using Caenorhabditis elegans. Our results indicated that ceramide was required for gamma radiation-induced whole-body germ cell apoptosis by the production of radical oxygen species and decrease of mitochondrial transmembrane potential. Using genetic ceramide synthase-related mutated strains and exogenous C16-ceramide, we illustrated that ceramide could regulate DNA damage response (DDR) pathway to mediate radiation-induced germ cell apoptosis. Moreover, ceramide was found to function epistatic to pmk-1 and mpk-1 in MAPK pathway to promote radiation-induced apoptosis in Caenorhabditis elegans. These results demonstrated ceramide could potentially mediated gamma radiation-induced apoptosis through regulating mitochondrial function, DDR pathway and MAPK pathway.


Asunto(s)
Caenorhabditis elegans/fisiología , Ceramidas/farmacología , Protectores contra Radiación/farmacología , Animales , Apoptosis/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de la radiación , Proteínas de Caenorhabditis elegans/genética , Ceramidas/metabolismo , Daño del ADN , Células Germinativas/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Radiación , Especies Reactivas de Oxígeno/metabolismo
16.
Ecotoxicol Environ Saf ; 208: 111725, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396056

RESUMEN

Aflatoxin B1 (AFB1) is a potent hepatotoxic and carcinogenic agent. Curcumin possesses potential anti-inflammatory, anti-oxidative and hepatoprotective effects. However, the role of LncRNAs in the protective mechanisms of curcumin against AFB1-induced liver damage is still elusive. Experimental broilers were randomly divided into 1) control group, 2) AFB1 group (1 mg/kg feed), 3) cur + AFB1 group (1 mg/kg AFB1 plus 300 mg/kg curcumin diet) and 4) curcumin group (300 mg/kg curcumin diet). Liver transcriptome analyses and qPCR were performed to identify shifts in genes expression. In addition, histopathological assessment and oxidant status were determined. Dietary AFB1 caused hepatic morphological injury, significantly increased the production of ROS, decreased liver antioxidant enzymes activities and induced inflammation and apoptosis. However, dietary curcumin partially attenuated the abnormal morphological changes, oxidative stress, and apoptosis in liver tissues. Transcriptional profiling results showed that 34 LncRNAs and 717 mRNAs were differentially expressed with AFB1 and curcumin co-treatment in livers of broilers. Analysis of the LncRNA-mRNA network, GO and KEGG enrichment data suggested that oxidative stress, inflammation and apoptosis pathway were crucial in curcumin's alleviating AFB1-induced liver damage. In conclusion, curcumin prevented AFB1-induced oxidative stress, inflammation and apoptosis through LncRNAs. These results provide new insights for unveiling the protective mechanisms of curcumin against AFB1-induced liver damage.


Asunto(s)
Aflatoxina B1/toxicidad , Curcumina/farmacología , Hígado/efectos de los fármacos , Sustancias Protectoras/farmacología , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Pollos/metabolismo , Dieta , Inflamación/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/farmacología
17.
Anticancer Res ; 41(1): 123-130, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419805

RESUMEN

BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is a serious disease and the leading cause of death globally. Overexpression of protein kinase B/nuclear factor-kappa B (NF-κB) signaling transduction of NSCLC cells was recognized as a potential therapeutic target. Lenvatinib is a multiple kinase inhibitor against vascular endothelial growth factor receptor family. However, whether lenvatinib may affect AKT/NF-κB in NSCLC remains unknown. MATERIALS AND METHODS: MTT assay, NF-κB reporter gene assay, flow cytometry, tranwell migration/invasion analysis and western blotting were used to identify the alteration of cell viability, NF-κB activation, apoptosis effect, migration/invasion potential and AKT/NF-κB related protein expression, respectively, in CL-1-5-F4 cells after lenvatinib treatment. RESULTS: The cell viability and NF-κB activity were suppressed by lenvatinib. Extrinsic and intrinsic apoptosis were activated by lenvatinib. Additionally, the metastatic potential of CL-1-5-F4 cells was also suppressed by lenvatinib. CONCLUSION: Altogether, lenvatinib induced extrinsic/intrinsic apoptosis and suppressed migration/invasion ability of NSCLC cells that was associated with AKT/NF-κB signaling inactivation.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/metabolismo , FN-kappa B/metabolismo , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos , Antineoplásicos/farmacología , Biomarcadores de Tumor , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Inhibidores de Proteínas Quinasas/farmacología
18.
Anticancer Res ; 41(1): 227-235, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419817

RESUMEN

BACKGROUND: 20(S)-Ginsenoside Rh2 (G-Rh2) has demonstrated therapeutic effects in many types of cancers. We aimed to investigate the potential anticancer activity and underlying mechanisms of G-Rh2 in oral cancer cells. MATERIALS AND METHODS: The antigrowth effect of G-Rh2 in oral cancer cells was stimulated by cell proliferation, soft agar colony formation, and migration and invasion assay. The cell cycle and apoptosis were detected by flow cytometry. The underlying mechanism of G-Rh2 in oral cancer cells was explored by immunoblotting. RESULTS: G-Rh2 significantly inhibited oral cancer cell growth by inducing apoptosis and cell cycle G0/G1-phase arrest. G-Rh2 inhibited oral cancer cell migration and invasion through regulation of epithelial-mesenchymal transition (EMT)-related proteins. G-Rh2 inhibited the Src/Raf/ERK signaling pathway in YD10B and Ca9-22 cells. CONCLUSION: G-Rh2 exerted anticancer activity in vitro by inhibiting the Src/Raf/ERK signaling pathway in oral cancer. G-Rh2 is a potential therapeutic drug for oral cancer treatment.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ginsenósidos/farmacología , Transducción de Señal/efectos de los fármacos , Quinasas raf/metabolismo , Familia-src Quinasas/metabolismo , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Ginsenósidos/química , Humanos , Neoplasias de la Boca/metabolismo
19.
Anticancer Res ; 41(1): 259-268, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33419820

RESUMEN

BACKGROUND/AIM: Quinazolinone is a privileged chemical structure employed for targeting various types of cancer. This study aimed to demonstrate the antitumor activity of synthesized 6,7-disubstituted-2-(3-fluorophenyl) quinazolines (HoLu-11 to HoLu-14). MATERIALS AND METHODS: The cytotoxicity was assessed by the sulforhodamine B (SRB) assay. The cell cycle was examined by flow cytometry. The expression levels of cell cycle- and apoptosis-related proteins were estimated by western blotting. A xenograft animal model was used to explore the antitumor effects of HoLu-12. RESULTS: Among four synthetic quinazolinone derivatives, HoLu-12 significantly reduced the viability of oral squamous cell carcinoma (OSCC) cells. HoLu-12 induced G2/M arrest and increased the expression of cyclin B, histone H3 (Ser10) phosphorylation, and cleaved PARP, indicating that HoLu-12 could induce mitotic arrest and then apoptosis. Moreover, the combination of HoLu-12 and 5-fluorouracil (5-FU) displayed synergistic toxic effect on OSCC cells. HoLu-12 significantly inhibited tumor growth in vivo. CONCLUSION: HoLu-12 induces mitotic arrest and leads to apoptosis of OSCC cells. Furthermore, HoLu-12 alone or in combination with 5-FU is a potential therapeutic agent for OSCC.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Quinazolinonas/farmacología , Animales , Antineoplásicos/química , Carcinoma de Células Escamosas , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Citometría de Flujo , Fluorouracilo/farmacología , Humanos , Ratones , Mitosis/efectos de los fármacos , Neoplasias de la Boca , Quinazolinonas/química , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Int J Biol Macromol ; 170: 688-700, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33385452

RESUMEN

Requirement for medication from pathogenic human viruses and cancer diseases are urgently considered, while, numerous reports were focused on investigating easily manufactured and excellently effective therapeutic reagents. Herein, CQDs were prepared with size of 2.1 nm from both of carrageenan and pullulan. CQDs nucleated from pullulan showed higher anti-proliferative effects against cancer cells, while, treatment with 100 µg/mL of CQDs colloids originated from pullulan and carrageenan separately resulted in diminishing of cancer cell viability percent to be 42.1 & 58.7%, respectively. Plaque reduction assay was also affirmed that, 2.5 µg/L of both of pullulan and carrageenan based CQDs exhibited viral inhibition with percent of 44.3& 59.5%, respectively. As a conclusion, pullulan showed seniority over carrageenan in nucleation of CQDs with higher anticancer activities. While, estimation of antiviral performance of the prepared CQDs confirmed the priority of carrageenan compared to pullulan in preparation of CQDs as antiviral laborer.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/química , Antivirales/farmacología , Puntos Cuánticos/química , Puntos Cuánticos/uso terapéutico , Apoptosis/efectos de los fármacos , Carbono/química , Carragenina/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Glucanos/química , Tecnología Química Verde , Humanos , Microscopía Electrónica de Transmisión , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Puntos Cuánticos/ultraestructura , Ensayo de Placa Viral
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