Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 71
Filtrar
1.
BMC Oral Health ; 24(1): 477, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643116

RESUMO

BACKGROUND: This study examines the oral health benefits of heat-killed Lacticaseibacillus paracasei GMNL-143, particularly its potential in oral microbiota alterations and gingivitis improvement. METHODS: We assessed GMNL-143's in vitro interactions with oral pathogens and its ability to prevent pathogen adherence to gingival cells. A randomized, double-blind, crossover clinical trial was performed on gingivitis patients using GMNL-143 toothpaste or placebo for four weeks, followed by a crossover after a washout. RESULTS: GMNL-143 showed coaggregation with oral pathogens in vitro, linked to its surface layer protein. In patients, GMNL-143 toothpaste lowered the gingival index and reduced Streptococcus mutans in crevicular fluid. A positive relationship was found between Aggregatibacter actinomycetemcomitans and gingival index changes, and a negative one between Campylobacter and gingival index changes in plaque. CONCLUSION: GMNL-143 toothpaste may shift oral bacterial composition towards a healthier state, suggesting its potential in managing mild to moderate gingivitis. TRIAL REGISTRATION: ID NCT04190485 ( https://clinicaltrials.gov/ ); 09/12/2019, retrospective registration.


Assuntos
Gengivite , Lacticaseibacillus paracasei , Microbiota , Adulto , Humanos , Índice de Placa Dentária , Método Duplo-Cego , Gengivite/tratamento farmacológico , Estudos Retrospectivos , Cremes Dentais/uso terapêutico , Estudos Cross-Over
2.
BMC Microbiol ; 23(1): 121, 2023 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-37120517

RESUMO

BACKGROUND: The equilibrium of the scalp microbiome is important for maintaining healthy scalp conditions, including sebum secretion, dandruff, and hair growth. Many different strategies to improve scalp health have been reported; however, the effect of postbiotics, such as heat-killed probiotics, on scalp health remains unclear. We examined the beneficial effects of heat-killed probiotics consisting of Lacticaseibacillus paracasei, GMNL-653, on scalp health. RESULTS: Heat-killed GMNL-653 could co-aggregate with scalp commensal fungi, Malassezia furfur, in vitro, and the GMNL-653-derived lipoteichoic acid inhibited the biofilm formation of M. furfur on Hs68 fibroblast cells. The mRNA of hair follicle growth factors, including insulin-like growth factor-1 receptor (IGF-1R), vascular endothelial growth factor, IGF-1, and keratinocyte growth factor was up-regulated in skin-related human cell lines Hs68 and HaCaT after treatment with heat-killed GMNL-653. For clinical observations, we recruited 22 volunteer participants to use the shampoo containing the heat-killed GMNL-653 for 5 months and subsequently measured their scalp conditions, including sebum secretion, dandruff formation, and hair growth. We applied polymerase chain reaction (PCR) to detect the scalp microbiota of M. restricta, M. globosa, Cutibacterium acnes, and Staphylococcus epidermidis. A decrease in dandruff and oil secretion and an increase in hair growth in the human scalp were observed after the use of heat-killed GMNL-653-containing shampoo. The increased abundance of M. globosa and the decreased abundance of M. restricta and C. acnes were also observed. We further found that accumulated L. paracasei abundance was positively correlated with M. globosa abundance and negatively correlated with C. acnes abundance. S. epidermidis and C. acnes abundance was negatively correlated with M. globosa abundance and positively correlated with M. restricta. Meanwhile, M. globosa and M. restricta abundances were negatively associated with each other. C. acnes and S. epidermidis abundances were statistically positively correlated with sebum secretion and dandruff, respectively, in our shampoo clinical trial. CONCLUSION: Our study provides a new strategy for human scalp health care using the heat-killed probiotics GMNL-653-containing shampoo. The mechanism may be correlated with the microbiota shift.


Assuntos
Caspa , Lacticaseibacillus paracasei , Microbiota , Humanos , Couro Cabeludo/microbiologia , Caspa/terapia , Caspa/microbiologia , Lacticaseibacillus , Temperatura Alta , Fator A de Crescimento do Endotélio Vascular
3.
Int J Mol Sci ; 23(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36499676

RESUMO

Pemetrexed is a folic acid inhibitor used as a second-line chemotherapeutic agent for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), which accounts for 85% of lung cancers. However, prolonged treatment with pemetrexed may cause cancer cells to develop resistance. In this study, we found increased expressions of BMI1 (B Lymphoma Mo-MLV insertion region 1 homolog) and Sp1 and a decreased expression of miR-145-5p was found in pemetrexed-resistant A400 cells than in A549 cells. Direct Sp1 targeting activity of miR-145-5p was demonstrated by a luciferase based Sp1 3'-UTR reporter. Changed expression of miR-145-5p in A400 or A549 cells by transfection of miR-145-5p mimic or inhibitor affected the sensitivity of the cells to pemetrexed. On the other hand, the overexpression of Sp1 in A549 cells caused the decreased sensitivity to pemetrexed, induced cell migratory capability, and epithelial-mesenchymal transition (EMT) related transcription factors such as Snail Family Transcriptional Repressor 1 and Zinc Finger E-Box Binding Homeobox 1. In addition, the overexpression of BMI1 in the A549 cells resulted in an increase in Sp1 and a decrease in miR-145-5p accompanied by the elevations of cell proliferation and EMT transcription factors, which could be reduced by the overexpression of miR-145-5p or by treatment with the Sp1 inhibitor of mithramycin A. In conclusion, the results of this study suggest that the downregulation of miR-145-5p by BMI1 overexpression could lead to the enhanced expression of Sp1 to induce the EMT process in pemetrexed-resistant NSCLC cells. These results suggest that increasing miR-145-5p expression by delivering RNA drugs may serve as a sensitizing agent for pemetrexed-resistant NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Transição Epitelial-Mesenquimal/genética , Pemetrexede/farmacologia , Pemetrexede/metabolismo , Pemetrexede/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Proliferação de Células/genética , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo
4.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362068

RESUMO

Differentiated thyroid carcinomas (DTCs), which have papillary and follicular types, are common endocrine malignancies worldwide. Cancer stem cells (CSCs) are a particular type of cancer cells within bulk tumors involved in cancer initiation, drug resistance, and metastasis. Cells with high intracellular aldehyde hydrogenase (ALDH) activity are a population of CSCs in DTCs. Disulfiram (DSF), an ALDH inhibitor used for the treatment of alcoholism, reportedly targets CSCs in various cancers when combined with copper. This study reported for the first time that DSF/copper can inhibit the proliferation of papillary and follicular DTC lines. DSF/copper suppressed thyrosphere formation, indicating the inhibition of CSC activity. Molecular mechanisms of DSF/copper involved downregulating the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and cell cycle-related proteins, including cyclin B2, cyclin-dependent kinase (CDK) 2, and CDK4, in a dose-dependent manner. BMI1 overexpression diminished the inhibitory effect of DSF/copper in the thyrosphere formation of DTC cells. BMI1 knockdown by RNA interference in DTC cells also suppressed the self-renewal capability. DSF/copper could inhibit the nuclear localization and transcriptional activity of c-Myc and the binding of E2F1 to the BMI1 promoter. Overexpression of c-Myc or E2F1 further abolished the inhibitory effect of DSF/copper on BMI1 expression, suggesting that the suppression of c-Myc and E2F1 by DSF/copper was involved in the downregulation of BMI1 expression. In conclusion, DSF/copper targets CSCs in DTCs by inhibiting c-Myc- or E2F1-mediated BMI1 expression. Therefore, DSF is a potential therapeutic agent for future therapy in DTCs.


Assuntos
Cobre , Dissulfiram , Células-Tronco Neoplásicas , Neoplasias da Glândula Tireoide , Humanos , Aldeído Desidrogenase/metabolismo , Linhagem Celular Tumoral , Cobre/química , Cobre/farmacologia , Dissulfiram/farmacologia , Dissulfiram/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo
5.
Int J Mol Sci ; 22(20)2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34681614

RESUMO

The l-type amino acid transporter 1 (LAT1) is a membranous transporter that transports neutral amino acids for cells and is dysregulated in various types of cancer. Here, we first observed increased LAT1 expression in pemetrexed-resistant non-small cell lung cancer (NSCLC) cells with high cancer stem cell (CSC) activity, and its mRNA expression level was associated with shorter overall survival in the lung adenocarcinoma dataset of the Cancer Genome Atlas database. The inhibition of LAT1 by a small molecule inhibitor, JPH203, or by RNA interference led to a significant reduction in tumorsphere formation and the downregulation of several cancer stemness genes in NSCLC cells through decreased AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) activation. The treatment of the cell-permeable leucine derivative promoted AKT/mTOR phosphorylation and reversed the inhibitory effect of JPH203 in the reduction of CSC activity in pemetrexed-resistant lung cancer cells. Furthermore, we observed that LAT1 silencing caused the downregulation of programmed cell death 1 ligand 1 (PD-L1) on lung cancer cells. The PD-L1+/LAT1+ subpopulation of NSCLC cells displayed great CSC activity with increased expression of several cancer stemness genes. These data suggest that LAT1 inhibitors can serve as anti-CSC agents and could be used in combination with immune checkpoint inhibitors in lung cancer therapy.


Assuntos
Antígeno B7-H1/metabolismo , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Benzoxazóis/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/química , Transportador 1 de Aminoácidos Neutros Grandes/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Pemetrexede/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Tirosina/análogos & derivados , Tirosina/farmacologia
6.
Int J Cancer ; 146(6): 1674-1685, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31340060

RESUMO

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.


Assuntos
Neoplasias da Mama/patologia , Células-Tronco Neoplásicas/patologia , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , Receptores de Estrogênio/genética , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares , Tamoxifeno/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína de Morte Celular Associada a bcl/metabolismo
7.
Bioorg Chem ; 100: 103904, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32413630

RESUMO

Phototriggered drug delivery systems (PTDDSs) facilitate controlled delivery of drugs loaded on photoactive platform to the target region under light stimulation. The present study investigated the synthesis and efficacy of carbazole-coumarin (CC)-fused heterocycles as a PTDDS platform for the photocontrolled release of a chemotherapeutic agent, chlorambucil, in an in vitro model of human breast and leukemia cancer cells. CC-fused heterocycles were constructed using 4-hydroxycarbazole as the starting material, and further modification of these heterocycles yielded two CC derivatives. CC-7 with an additional - COOH group and CC-8 with the triphenylphosphonium (TPP) group, a mitochondria-targeting ligand introduced in the carbazole ring, dissolved in polar solvents and exhibited emission bands at 360 and 450 nm, respectively. The results indicate that visible light of 405 nm triggers the photolysis of the CC-drug conjugate and efficiently delivers the drug in both in vitro cancer cell models. Cytotoxicity evaluation indicates the suppression of proliferation of both types of cells treated with CC-8 under synergy effect combining drug potency and photosensitization. Further, the lower IC50 of CC-8 toward leukemia cells suggests the efficacy of the TPP ligand in increasing the bioavailability of CC-drug conjugates in leukemia treatment. Studies on mitochondria-targeting drug delivery systems are required for improving the performance of anticancer drugs.


Assuntos
Antineoplásicos/administração & dosagem , Carbazóis/química , Clorambucila/administração & dosagem , Cumarínicos/química , Preparações de Ação Retardada/química , Leucemia/tratamento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Clorambucila/farmacocinética , Clorambucila/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Luz
8.
Int J Med Sci ; 17(14): 2214-2224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922184

RESUMO

Radioresistant cells cause recurrence in patients with breast cancer after they undergo radiation therapy. The molecular mechanisms by which cancer cells obtain radioresistance should be understood to develop radiation-sensitizing agents. Results showed that the protein expression and activity of NAD(P)H:quinone oxidoreductase 1 (NQO1) were upregulated in radioresistant MDA-MB-231 triple-negative breast cancer (TNBC) cells. NQO1 knockdown inhibited the proliferation of NQO1 expressing Hs578t TNBC cells or the radioresistant MDA-MB-231 cells, whereas NOQ1 overexpression increased the survival of MDA-MB-231 cells, which lack of NQO1 expression originally, under irradiation. The cytotoxicity of ß-lapachone, an NQO1-dependent bioactivatable compound, was greater in radioresistant MDA-MB-231 cells than in parental cells. ß-lapachone displayed a radiosensitization effect on Hs578t or radioresistant MBDA-MB-231 cells. The expression of the long noncoding RNA NEAT1 positively regulated the NQO1 expression in radioresistant MDA-MB-231 cells at a translational level rather than at a transcription level. The inhibition of the NEAT1 expression through the CRISPR-Cas9 method increased the sensitivity of radioresistant MDA-MB-231 cells to radiation and decreased their proliferation, the activity of cancer stem cells, and the expression of stemness genes, including BMI1, Oct4, and Sox2. In conclusion, the NQO1 expression in triple-negative breast cancer cells determined their radiosensitivity and was controlled by NEAT1. In addition, NOQ1 bioactivatable compounds displayed potential for application in the development of radiation sensitizers in breast cancer.


Assuntos
NAD(P)H Desidrogenase (Quinona)/genética , RNA Longo não Codificante/metabolismo , Tolerância a Radiação/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/genética , Sobrevivência Celular/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Técnicas de Silenciamento de Genes , Humanos , NAD(P)H Desidrogenase (Quinona)/metabolismo , Naftoquinonas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , RNA Longo não Codificante/genética , Radiossensibilizantes/farmacologia , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
9.
Int J Med Sci ; 15(6): 574-579, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725247

RESUMO

Chemotherapy is one of effective methods for the treatment of tumor. Patients often develop drug resistance after chemotherapic cycles. Salmonella has potential as antitumor agent. Salmonella used in tandem with chemotherapy had additive effects, providing a rationale for using tumor-targeting Salmonella in combination with conventional chemotherapy. To improve the efficacy and safety of Salmonella, a further understanding of Salmonella interactions with the tumor microenvironment is required. The presence of plasma membrane multidrug resistance protein P-glycoprotein (P-gp) is highly relevant for the success of chemotherapy. Following Salmonella infection, dose-dependent downregulation of P-gp expressions were examined. Salmonella significantly decreased the efflux capabilities of P-gp, as based on the influx of Rhodamine 123 assay. In addition, Salmonella significant reduced the protein express the expression levels of phosph-protein kinase B (P-AKT), phosph-mammalian targets of rapamycin (P-mTOR), and phosph-p70 ribosomal s6 kinase (P-p70s6K) in tumor cells. The Salmonella-induced downregulation of P-gp was rescued by transfection of cells with active P-AKT. Our results demonstrate that Salmonella in tumor sites leads to decrease the expression of P-gp and enhances the combination of Salmonella and 5-Fluorouracil therapeutic effects.


Assuntos
Fluoruracila/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/microbiologia , Infecções por Salmonella/genética , Salmonella/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/genética , Terapia Combinada , Resistência a Múltiplos Medicamentos/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Melanoma Experimental/patologia , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Salmonella/patogenicidade , Infecções por Salmonella/microbiologia , Infecções por Salmonella/patologia , Serina-Treonina Quinases TOR/genética , Microambiente Tumoral/efeitos dos fármacos
10.
Int J Med Sci ; 14(12): 1181-1188, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29104473

RESUMO

Upregulation of connexin 43 (Cx43) showed potential in enhancing immune surveillance that was suppressed in the tumor microenvironment. The expression of indoleamine 2, 3-dioxygenase (IDO) is one of the crucial factors contributing to tumor immune tolerance by depletion of tryptophan and IDO-mediated tryptophan metabolites. Here, we aim to investigate the role of Cx43 in IDO production in murine tumor by using Cx43 inducers. Resveratrol (trans-3, 5, 4 '-trihydroxystilbene) is a natural plant-derived polyphenol possessing positive effect against cancer. Salmonella enterica serovar choleraesuis (S.C.) was proved to target and inhibit tumor growth. Both of them regulated Cx43 expression in tumor cells and led to either chemosensitizing or immune-activating. In this study, the correlation between Cx43 and IDO were determined by the treatment of resveratrol and S.C. Our data showed an increase in Cx43 while IDO protein and IDO-mediated inhibited effects on T cell decreased after tumor cells are given with resveratrol and S.C. TREATMENTS: All of which could be inhibited once the expression of Cx43 was blocked. Cx43 involved in IDO regulation might be useful in developing IDO-targeted cancer immune therapy.


Assuntos
Conexina 43/imunologia , Tolerância Imunológica/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Conexina 43/genética , Conexina 43/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Tolerância Imunológica/efeitos dos fármacos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Neoplasias/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Resveratrol , Salmonella enterica/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Estilbenos/farmacologia , Regulação para Cima
11.
Int J Mol Sci ; 18(9)2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28914785

RESUMO

Heat shock protein 90 (Hsp90) is a molecular chaperone that facilitates the correct folding and functionality of its client protein. Numerous Hsp90-client proteins are involved in cancer development. Thus, Hsp90 inhibitors have potential applications as anti-cancer drugs. We previously discovered that Hsp90α expression increased in breast cancer stem cells (BCSCs), which can initiate tumorigenesis and metastasis and resist treatment. In the present study, we further demonstrated that 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an inhibitor of Hsp90, could suppress the self-renewal of BCSCs by downregulating B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a polycomb family member with oncogenic activity in breast cancer. Through immunoprecipitation analysis, we found that BMI1 did not interact with Hsp90α and that the downregulation of BMI1 by 17-DMAG was mediated by the inhibition of c-Myc and enhancement of zeste homolog 2 (EZH2) expression. The transcriptional and BMI1 promoter-binding activities of c-Myc in BCSCs were inhibited by 17-DMAG treatment. The overexpression of EZH2 attenuated the inhibitory effect of 17-DMAG on BMI1 and c-Myc expression. Furthermore, Hsp90α could be co-immunoprecipitated with c-Myc and EZH2 and bind to the BMI1 promoter. Treatment with 17-DMAG decreased the nuclear expression of EZH2 and c-Myc but not that of Hsp90α. In conclusion, our data suggested that Hsp90α could positively regulate the self-renewal of BCSCs by facilitating the nuclear translocation of c-Myc and EZH2 to maintain BMI1 expression.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Benzoquinonas/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactamas Macrocíclicas/farmacologia , Ligação Proteica , Transporte Proteico , Proteínas Proto-Oncogênicas c-myc/genética , Transcrição Gênica
12.
Environ Toxicol ; 31(1): 77-84, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25044443

RESUMO

Hinokitiol is found in the heartwood of cupressaceous plants and possesses several biological activities. Hinokitiol may play an important role in anti-inflammation and antioxidant processes, making it potentially useful in therapies for inflammatory-mediated disease. Previously, the suppression of tumor growth by hinokitiol has been shown to occur through apoptosis. Programmed cell death can also occur through autophagy, but the mechanism of hinokitiol-induced autophagy in tumor cells is poorly defined. We used an autophagy inhibitor (3-methyladenine) to demonstrate that hinokitiol can induce cell death via an autophagic pathway. Further, we suggest that hinokitiol induces autophagy in a dose-dependent manner. Markers of autophagy were increased after tumor cells were treated with hinokitiol. In addition, immunoblotting revealed that the levels of phosphoprotein kinase B (P-AKT), phosphomammalian target of rapamycin (P-mTOR), and phospho-p70 ribosomal s6 kinase (P-p70S6K) in tumor cells were decreased after hinokitiol treatment. In conclusion, our results indicate that hinokitiol induces the autophagic signaling pathway via downregulation of the AKT/mTOR pathway. Therefore, our findings show that hinokitiol may control tumor growth by inducing autophagic signaling.


Assuntos
Autofagia/efeitos dos fármacos , Monoterpenos/toxicidade , Tropolona/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Camundongos , Monoterpenos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tropolona/uso terapêutico , Tropolona/toxicidade
13.
Int J Mol Sci ; 17(7)2016 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399693

RESUMO

Oral squamous cell carcinoma (OSCC) is the most common malignancy of head and neck. Although radiotherapy is used for OSCC treatment, the occurrence of radioresistant cancer cells limits its efficiency. MicroRNAs (miRNAs) are non-coding RNAs with lengths of 18-25 base pairs and known to be involved in carcinogenesis. We previously demonstrated that by targeting B lymphoma Mo-MLV insertion region 1 homolog (Bmi1), miR-494-3p functions as a putative tumor suppressor miRNA in OSCC. In this study, we further discovered that miR-494-3p could enhance the radiosensitivity of SAS OSCC cells and induce cellular senescence. The overexpression of miR-494-3p in SAS cells increased the population of senescence-associated ß-galactosidase positive cells, the expression of p16(INK4a) and retinoblastoma 1 (RB1), as well as downregulated Bmi1. The knockdown of Bmi1 by lentiviral-mediated delivery of specific short hairpin RNAs (shRNAs) also enhanced the radiosensitivity of SAS cells and the activation of the senescence pathway. Furthermore, the inverse correlation between Bmi1 and miR-494-3p expression was observed among OSCC tissues. Results suggest that miR-494-3p could increase the radiosensitivity of OSCC cells through the induction of cellular senescence caused by the downregulation of Bmi1.


Assuntos
Carcinoma de Células Escamosas/patologia , Senescência Celular , MicroRNAs/metabolismo , Neoplasias Bucais/patologia , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Sequência de Bases , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação para Baixo , Raios gama , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neoplasias Bucais/metabolismo , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Tolerância a Radiação , Proteína 1 de Ligação ao Retinoblastoma/metabolismo , Alinhamento de Sequência , beta-Galactosidase/metabolismo
14.
Stem Cells ; 32(8): 2048-60, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24802135

RESUMO

Overexpression of SH2-containing-5'-inositol phosphatase-2 (SHIP2) correlates with poor survival in breast cancer. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here, we showed that the percentage of SHIP2(+) cells was positively correlated with that of CD24(-) CD44(+) cells in 60 breast cancer specimens. Among 20 estrogen receptor (ER)-negative samples, 17 had greater SHIP2 expression in CD24(-) CD44(+) subpopulation than the remaining subpopulation. Data mining of microarray analysis of 295 breast tumors showed a significant correlation of higher SHIP2 expression with distant metastasis. Examination of patient-derived mouse xenografts revealed that SHIP2 protein and its tyrosine 1135 phosphorylation were significantly higher in BCSCs, identified as CD24(-) CD44(+) or aldehyde dehydrogenase (ALDH(+)), than non-BCSCs. SHIP2 silencing or inhibitor of SHIP2 phosphatase significantly decreased mammosphere-forming efficiency, ALDH(+) subpopulation in vitro and tumorigenicity of BCSCs in vivo. Overexpression of SHIP2 enhanced the expression of epithelial-mesenchymal transition markers including vimentin (VIM), which was mainly expressed in ER-negative breast cancer cells with higher level in mammospheres than monolayer culture. Ablation of c-Jun N-terminal kinase 1 (JNK1), JNK2, or VIM diminished the increased ALDH(+) population and tumorigenicity, induced by SHIP2 overexpression. BCSCs displayed greater expression of phospho-JNK than non-BCSCs and silencing of JNK suppressed SHIP2-mediated upregulation of VIM. Furthermore, SHIP2 overexpression enhanced Akt activation, but Akt inhibition failed to influence SHIP2-induced phospho-JNK/VIM upregulation. In conclusion, SHIP2 plays a key role in BCSCs of ER-negative breast cancers through activation of Akt and JNK with upregulation of VIM and may serve as a target for therapy directed at BCSCs.


Assuntos
Neoplasias da Mama/patologia , MAP Quinase Quinase 4/metabolismo , Células-Tronco Neoplásicas/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Vimentina/metabolismo , Animais , Western Blotting , Neoplasias da Mama/metabolismo , Ativação Enzimática/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Citometria de Fluxo , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Estrogênio/biossíntese
15.
Environ Toxicol ; 30(8): 877-86, 2015 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-24449132

RESUMO

Although current studies indicate that resveratrol exhibits potential antitumor activities, the precise mechanisms of its beneficial effects combined with chemotherapy are not fully understood. This work is warranted to elucidate the underlying mechanism of antitumor effects by the combination therapy of resveratrol and cisplatin. The presence of functional gap junctions is highly relevant for the success of chemotherapy. Gap junctions mediate cell communication by allowing the passage of molecules from one cell to another. Connexin (Cx) 43 is ubiquitous and reduced in a variety of tumor cells. Cx43 may influence the response of tumor cells to treatments by facilitating the passage of antitumor drugs or death signals between neighboring tumor cells. Following resveratrol treatment, dose-dependent upregulation of Cx43 expressions was observed. In addition, gap junction intercellular communication was increased. To study the mechanism underlying these resveratrol-induced Cx43 expressions, we found that resveratrol induced a significant increase in mitogen-activated protein kinases (MAPK) signaling pathways. The MAPK inhibitors significantly reduced the expression of Cx43 protein after resveratrol treatment. Specific knockdown of Cx43 resulted in a reduction of cell death after resveratrol and cisplatin treatment. Our results suggest that treatment of resveratrol in tumor leads to increase Cx43 gap junction communication and enhances the combination of resveratrol and cisplatin therapeutic effects. © 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 877-886, 2015.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Conexina 43/biossíntese , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Estilbenos/farmacologia , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Conexina 43/genética , Relação Dose-Resposta a Droga , Junções Comunicantes/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
16.
J Cell Mol Med ; 18(4): 698-708, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24400868

RESUMO

Oral submucous fibrosis (OSF) is considered as a pre-cancerous condition of the oral mucosa and is highly associated with habitual areca quid chewing. Arecoline is the major alkaloid in areca quid and is thought to be involved in the pathogenesis of OSF. Our previous studies have demonstrated that arecoline could induce epithelial-mesenchymal transition (EMT)-related factors in primary human buccal mucosal fibroblasts (BMFs). Therefore, we investigated the expression of zinc finger E-box binding homeobox 1 (ZEB1), which is a well-known transcriptional factor in EMT, in OSF tissues and its role in arecoline-induced myofibroblast transdifferentiation from BMFs. The expression of ZEB1, as well as the myofibroblast marker α-smooth muscle actin (α-SMA), was significantly increased in OSF tissues, respectively. With immunofluorescence analysis, arecoline induced the formation of α-SMA-positive stress fibres in BMFs expressing nuclear ZEB1. Arecoline also induced collagen contraction of BMFs in vitro. By chromatin immunoprecipitation, the binding of ZEB1 to the α-SMA promoter in BMFs was increased by arecoline. The promoter activity of α-SMA in BMFs was also induced by arecoline, while knockdown of ZEB1 abolished arecoline-induced α-SMA promoter activity and collagen contraction of BMFs. Long-term exposure of BMFs to arecoline induced the expression of fibrogenic genes and ZEB1. Silencing of ZEB1 in fibrotic BMFs from an OSF patient also suppressed the expression of α-SMA and myofibroblast activity. Inhibition of insulin-like growth factor receptor-1 could suppress arecoline-induced ZEB1 activation in BMFs. Our data suggest that ZEB1 may participate in the pathogenesis of areca quid-associated OSF by activating the α-SMA promoter and inducing myofibroblast transdifferentiation from BMFs.


Assuntos
Arecolina/administração & dosagem , Transdiferenciação Celular/efeitos dos fármacos , Proteínas de Homeodomínio/biossíntese , Fibrose Oral Submucosa/patologia , Fatores de Transcrição/biossíntese , Actinas/biossíntese , Actinas/genética , Areca/química , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Fibroblastos/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Humanos , Mastigação , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Miofibroblastos/efeitos dos fármacos , Fibrose Oral Submucosa/induzido quimicamente , Fibrose Oral Submucosa/metabolismo , Cultura Primária de Células , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco
17.
Biochem Cell Biol ; 92(5): 397-405, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25264079

RESUMO

Astragalus membranaceus, a traditional Chinese herb, has been used to improve airway inflammation and asthma. The present study investigated whether A. membranaceus has immunotherapeutic effects on asthma, a chronic inflammatory mucosal disease that is associated with excess production of IgE, eosinophilia, T helper 2 (Th2) cytokines, and bronchial hyperresponsiveness. An ovalbumin (OVA)-induced, chronic inflammatory airway murine asthma model was used to examine the status of pulmonary inflammation after the administration of A. membranaceus. The IgE levels in serum and bronchoalveolar lavage fluid showed a tendency to decrease after the administration of A. membranaceus. The number of eosinophils decreased and infiltration of inflammatory cells and collagen deposition declined in lung sections after A. membranaceus administration. The RNA and protein levels of Th2 cytokines and the ratio of the GATA3/T-bet mRNA levels decreased after A. membranaceus treatment. Furthermore, the mRNA level of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor, increased in the lung tissues of A. membranaceus-treated mice. Finally, an A. membranaceus water extract activated PPARγ activity in either human embryonic kidney 293 (HEK293) or A549 cells in a PPARγ-responsive element-containing luciferase reporter assay. These results indicate that A. membranaceus has an inhibitory effect on airway inflammation in a murine model of asthma through modulating the imbalanced relationship between Th1 and Th2 cytokines.


Assuntos
Asma/tratamento farmacológico , Asma/imunologia , Astragalus propinquus , PPAR gama/metabolismo , Fitoterapia , Equilíbrio Th1-Th2/efeitos dos fármacos , Animais , Asma/fisiopatologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Fator de Transcrição GATA3/metabolismo , Células HEK293 , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-13/sangue , Interleucina-4/sangue , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos , Extratos Vegetais/uso terapêutico
18.
Cell Tissue Res ; 358(2): 551-66, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25130140

RESUMO

Homeobox genes encode transcription factors that regulate embryonic development programs including organogenesis, axis formation and limb development. Previously, we identified and cloned a mouse double homeobox gene, Duxbl, whose homeodomain exhibits the highest identity (67 %) to human DUX4, a candidate gene of facioscapulohumeral muscular dystrophy (FSHD). Duxbl proteins have been shown to be expressed in elongated myocytes and myotubes of trunk and limb muscles during embryogenesis. In this study, we found that Duxbl maintained low expression levels in various adult muscles. Duxbl proteins were induced to express in activated satellite cells and colocalized with MyoG, a myogenic differentiating marker. Furthermore, Duxbl proteins were not detected in quiescent satellite cells but detected in regenerated myocytes and colocalized with MyoD and MyoG following cardiotoxin-induced muscle injury. Ectopic Duxbl overexpressions in C2C12 myoblast cells promoted cell proliferation through mainly enhancing cyclin D1 and hyper-phosphorylated retinoblastoma protein but reducing p21 expression. However, Duxbl overexpression in C2C12 cells inhibited myogenic differentiation by decreasing MyoD downstream gene expressions, including M-cadherin, MyoG, p21 and cyclin D3 but not MyoD itself. Duxbl overexpressions also promoted cell proliferation but blocked MyoD-induced myogenic conversion in multipotent mesenchymal C3H10T1/2 cells. In addition, results of a luciferase reporter assay suggest that Duxbl negatively regulated MyoG promoter activity through the proximal two E boxes. In conclusion, these results indicate that Duxbl may play a crucial role in myogenesis and postnatal muscle regeneration by activating and proliferating satellite and myoblast cells.


Assuntos
Diferenciação Celular , Proteínas de Homeodomínio/genética , Proteína MyoD/genética , Mioblastos/citologia , Mioblastos/metabolismo , Fatores de Transcrição/genética , Ativação Transcricional/genética , Envelhecimento/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Imunofluorescência , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos , Desenvolvimento Muscular , Proteína MyoD/metabolismo , Miogenina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regeneração , Células Satélites de Músculo Esquelético/metabolismo , Fatores de Transcrição/metabolismo
19.
Int J Mol Sci ; 15(8): 14546-54, 2014 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-25196596

RESUMO

Lack of specificity of the therapeutic agent is a primary limitation in the treatment of a tumor. The use of preferentially replicating bacteria as therapeutic agents is an innovative approach to tumor treatment. This is based on the observation that certain obligate or facultative anaerobic bacteria are capable of multiplying selectively in tumors and inhibiting their growth. Bacteria have been employed as antitumor agents that are capable of preferentially amplifying within tumors and inhibiting their growth. Moreover, bacteria-derived factors have an immune-stimulation effect. Therefore, bacteria are able to transfer therapeutic genes into the tumor cells using their infective ability. Herein, we introduce the application of bacteria for tumor therapy and focus on Salmonella, which have been widely used for tumor therapy. Salmonella have mainly been applied as gene-delivery vectors, antitumor immune activators and tumor cell death inducers. This study will not only evaluate the therapeutic efficacy of Salmonella for the treatment of tumor but will also elucidate the mechanisms underlying the antitumor activities mediated by Salmonella, which involve host immune responses and cellular molecular responses.


Assuntos
Neoplasias/terapia , Salmonella/metabolismo , Salmonella/fisiologia , Animais , Antineoplásicos , Humanos , Imunoterapia , Salmonella/genética
20.
Int J Biol Sci ; 20(1): 265-279, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38164180

RESUMO

Endometrial carcinoma (EC) is a common type of uterine cancer in developed countries, originating from the uterine epithelium. The incidence rate of EC in Taiwan has doubled from 2005. Cancer stem cells (CSCs) are a subpopulation of cancer cells that have high tumorigenicity and play a crucial role in the malignant processes of cancer. Targeting molecules associated with CSCs is essential for effective cancer treatments. This study delves into the role of Exosome component 5 (EXOSC5) in EC. Data from The Cancer Genome Atlas suggests a correlation between high EXOSC5 mRNA expression and unfavorable EC prognosis. EXOSC5 knockdown diminished EC-CSC self-renewal and reduced expression of key cancer stemness proteins, including c-MYC and SOX2. Intriguingly, this knockdown significantly curtailed tumorigenicity and CSC frequency in EC tumor spheres. A mechanistic examination revealed a reduction in netrin4 (NTN4) levels in EXOSC5-depleted EC cells. Moreover, NTN4 treatment amplified EC cell CSC activity and, when secreted, NTN4 partnered with integrin ß1, subsequently triggering the FAK/SRC axis to elevate c-MYC activity. A clear positive relation between EXOSC5 and NTN4 was evident in 93 EC tissues. In conclusion, EXOSC5 augments NTN4 expression, activating c-MYC via the integrin ß1/FAK/SRC pathway, offering potential avenues for EC diagnosis and treatment.


Assuntos
Neoplasias do Endométrio , Integrina beta1 , Humanos , Feminino , Integrina beta1/metabolismo , Transdução de Sinais/genética , Neoplasias do Endométrio/metabolismo , Células-Tronco Neoplásicas/metabolismo , Linhagem Celular Tumoral , Antígenos de Neoplasias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Netrinas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA