Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30.358
Filtrar
1.
Am J Chin Med ; 48(6): 1491-1509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32924531

RESUMO

Astragalus membranaceus is the most popular traditional Chinese medicine for managing vital energy deficiency. Its injectable polysaccharide PG2 has been used for relieving cancer-related fatigue, and PG2 has immune-modulatory and anti-inflammatory effects. In this study, we explored the effects of PG2 in lung adenocarcinoma A549 and CL1-2 cells and investigated its anticancer activity, and the results were validated in severe combined immunodeficiency (SCID) mice. Although PG2 did not inhibit the growth of these cells, it dose-dependently suppressed their migration and invasion, accompanied by reduced vimentin and AXL and induced epithelial cadherin (E-cadherin) expression. Regarding the underlying molecular mechanism, PG2 treatment reduced the macrophage migration inhibitory factor (MIF), an inflammatory cytokine that promotes the epithelial-mesenchymal transition and aggressiveness of cancer cells. Consistent with the previous finding that MIF regulates matrix metalloproteinase-13 (MMP-13) and AMP-activated protein kinase (AMPK), treatment with PG2 reduced MMP-13 and activated AMPK in A549 and CL1-2 cells in this study. In SCID mice injected with A549 cells through the tail vein, intraperitoneal injection with PG2 reduced lung and abdominal metastases in parallel with decreased immunohistochemical staining of AXL, vimentin, MMP-13, and MIF in the tumor. Collectively, data revealed a potential application of PG2 in integrative cancer treatment through the suppression of MIF in cancer cells and their aggressiveness.


Assuntos
Adenocarcinoma/patologia , Astragalus propinquus/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Oxirredutases Intramoleculares/metabolismo , Neoplasias Pulmonares/patologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fitoterapia , Polissacarídeos/administração & dosagem , Polissacarídeos/farmacologia , Células A549 , Adenocarcinoma/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Injeções Intraperitoneais , Neoplasias Pulmonares/metabolismo , Camundongos SCID , Invasividade Neoplásica , Polissacarídeos/isolamento & purificação , Polissacarídeos/uso terapêutico
2.
Ecotoxicol Environ Saf ; 205: 111327, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961493

RESUMO

Exposure to PM2.5 can cause serious harm to the respiratory system. Until now, although many toxicological studies have shown that pulmonary fibrosis can be caused by long-term PM2.5 exposure, there is no evidence that Endothelial-Mesenchymal Transition (EndMT) can trigger the process of pulmonary fibrosis after exposure. LncRNAs are a class of non-coding RNAs detected in mammalian cells. Nevertheless, researchers have not found whether lncRNAs participate in PM2.5 induced EndMT during pathophysiological duration. The Balb/c mouse model was exposed to PM2.5 for 4 months by dynamic intoxication. The levels of specific endothelial and mesenchymal markers were evaluated by molecular biology experiments to elucidate the mechanisms of EndMT induced by PM2.5 in lung tissues. LncRNA microarray analysis of the established mouse model of PM2.5 exposure was performed. Based on a bioinformatics analysis and RT-qPCR analysis, lncRNA Gm16410 attracted our attention. The change of lncRNA Gm16410 in mouse pulmonary vascular endothelial cells (MHCs) exposed to PM2.5 was verified, and the mechanism of lncRNA Gm16410 in EndMT was discussed. The changes of cell function were evaluated by cell migration and proliferation experiments. The molecular biology experiments proved that PM2.5 induced EndMT by activating the TGF-ß1/Smad3/p-Smad3 pathway in vitro. The relationship of EndMT and lncRNA Gm16410 was verified in mouse lung tissues and MHC cells by PM2.5 exposure. The involvement of lncRNA Gm16410 in PM2.5-induced EndMT highlights the potential of lncRNA to promote pulmonary fibrosis under environmental pollution.


Assuntos
Material Particulado/toxicidade , RNA Longo não Codificante/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Camundongos , Material Particulado/metabolismo , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3 , Fator de Crescimento Transformador beta1/metabolismo
3.
Anticancer Res ; 40(10): 5539-5544, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988877

RESUMO

BACKGROUND/AIM: Endothelin-1 (ET-1) is overexpressed in many types of cancer, inhibiting the release of the microRNA 15a (miR-15a) and inducing the production of Mxi-2. Our aim was to identify a molecular complex regulating p53 activity in prostate cancer (PCa). MATERIALS AND METHODS: DU145 cells were treated with ET-1, MAPK p38 inhibitor, Endothelin A receptor inhibitor (ETAR inhibitor) and Endothelin B receptor inhibitor (ETBR inhibitor). Extracts were analysed using Western Blot, immunoprecipitation and qRT-PCR. Furthermore, prostate cancer patient samples were analysed using qRT-PCR and ELISA. RESULTS: The hypothesised molecular complex was identified, with miR-15a, microRNA 1285 (miR-1285) and Mxi-2 levels up-regulated in patients in relation to increasing aggressiveness of PCa. CONCLUSION: A complex composed of Argonaut 2 (Ago2)/Mxi-2/miR-1285 is involved in PCa. The expression of Mxi-2 correlates with increasing PCa aggressiveness and might be used as a non-invasive marker for the diagnosis and progression of PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Quinase 14 Ativada por Mitógeno/genética , Neoplasias da Próstata/genética , Proteína Supressora de Tumor p53/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Argonauta/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Humanos , Masculino , MicroRNAs/genética , Neoplasias da Próstata/patologia , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
4.
Anticancer Res ; 40(10): 5611-5620, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988885

RESUMO

BACKGROUND/AIM: Cancer stem cell characteristics and drug resistance of colorectal cancer are associated with failure of cancer treatment. In this study, we investigated the effects of PrPC on cancer stem cell characteristics, migration, invasion, and drug resistance of 5FU-resistant CRC cells. MATERIALS AND METHODS: PrPC negative and PrPC positive cells were isolated from 5FU-resistant CRC cells using magnetic activated cell sorting. Sphere formation, cancer stem cell marker expression, migration, invasion, and drug resistance were analyzed. RESULTS: PrPC positive cells showed increased sphere formation capacity and increased expression of cancer stem cell markers compared to PrPC negative cells. In addition, PrPC positive cells showed increased migration, invasion and drug resistance compared to PrPC negative cells. Furthermore, knockdown of PrPC abolished these effects. CONCLUSION: PrPC expression is important in CRC cell behavior, such as sphere formation, migration, invasion, and drug resistance. PrPC is an important therapeutic target for the treatment of CRC.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Proteínas Priônicas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/genética , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos
5.
Anticancer Res ; 40(9): 5025-5033, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878790

RESUMO

BACKGROUND/AIM: This study aimed to investigate the effect of a new 7-(4-(N-substituted carbamoylmethyl) piperazin-1-yl) ciprofloxacin-derivative on the proliferation and migration abilities of HeLa cells. MATERIALS AND METHODS: Cell viability and morphological alterations were examined. Changes in migration were detected using wound healing and colony formation assays. Flow cytometry and western blotting were used to investigate the molecular mechanisms underlying this ciprofloxacin-derivative's action in HeLa cells. RESULTS: The examined ciprofloxacin-derivative reduced viability of HeLa cells in a concentration-dependent manner and altered cellular morphology, indicating cell death. Furthermore, it significantly inhibited wound closure, even in a non-cytotoxic concentration, and reduced HeLa cell colony formation. In addition, apoptosis was increased probably through significant up-regulation of Bax protein expression and the generation of active cleaved caspase-3 protein. CONCLUSION: Our new derivative inhibits proliferation and induces apoptosis of HeLa cells. Furthermore, it suppressed the migration and colony formation abilities of HeLa cells. Therefore, it represents an attractive agent for drug development against cervical cancer based on its anti-metastatic effect.


Assuntos
Antineoplásicos/farmacologia , Ciprofloxacino/análogos & derivados , Ciprofloxacino/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciprofloxacino/química , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Estrutura Molecular , Ensaio Tumoral de Célula-Tronco
6.
Anticancer Res ; 40(9): 5043-5048, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878792

RESUMO

BACKGROUND/AIM: Eicosapentaenoic acid (EPA) inhibits NF-ĸB activation and IL-6 production in TE-1 esophageal cancer cells. NF-ĸB is related to cancer cell migration. The aim of this study is to evaluate whether EPA has a metastasis suppressing effect. Herein, we investigated EPA-treated TE-1 cell migration using TAXIScan. MATERIALS AND METHODS: EZ-TAXIScan® was used to verify whether EPA inhibits cancer cell chemotaxis. RESULTS: Using 50% fetal bovine serum (chemoattractant) without EPA (positive control), average velocity was 0.306±0.084 µm/min compared to 0.162±0.067 µm/min without chemoattraction (negative control). Directionalities of positive and negative controls were 1.039±0.152 and 0.488±0.251 radians, respectively, indicating a significant increase in migration of the positive control compared to that of the negative control. Average velocities were 0.306±0.084 (no EPA), 0.288±0.078 (100 µM EPA), and 0.240±0.054 200 µM (EPA) µm/min, indicating that EPA reduced velocity dose-dependently. Average directionalities were 1.039±0.152 (no EPA), 0.967±0.164 (100 µM EPA), and 0.901±0.146 (200 µM EPA) radians, indicating that EPA also inhibited directionality dose-dependently. CONCLUSION: EPA suppresses directional migration of TE-1 cells.


Assuntos
Antineoplásicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quimiotaxia/efeitos dos fármacos , Ácido Eicosapentaenoico/química , Carcinoma de Células Escamosas do Esôfago , Humanos
7.
Anticancer Res ; 40(9): 5059-5069, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878794

RESUMO

BACKGROUND/AIM: Liver cancer is the fourth leading cause of cancer-related mortality globally, of which hepatocellular carcinoma (HCC) accounts for 85-90% of total primary liver cancer. A drug shortage for HCC therapy triggered us to screen the small-molecule database with a high-throughput cellular screening system. Herein, we examined whether cetyltrimethylammonium bromide (CTAB) inhibits cellular mobility and invasiveness of Mahlavu HCC cells. MATERIALS AND METHODS: The effects of CTAB on cell viability were assessed using WST-1 assay, cell-cycle distribution using flow cytometric analysis, migration/invasion using woundhealing and transwell assays, and associated protein levels using western blotting. RESULTS: Treatment of Mahlavu cells with CTAB transformed its mesenchymal spindle-like morphology. In addition, CTAB exerted inhibitory effects on the migration and invasion of Mahlavu cells dose-dependently. CTAB also reduced the protein levels of matrix metalloproteinase-2 (MMP2), MMP9, RAC family small GTPase 1, SNAIL family transcriptional repressor 1 (SNAI1), SNAI2, TWIST family basic helix-loop-helix transcription factor 1 (TWIST1), vimentin, N-cadherin, phospho-fibroblast growth factor (FGF) receptor, phospho-phosphoinositide 3-kinase, phospho-v-Akt murine thymoma viral oncogene and phospho-signal transducer and activator of transcription 3 but increased the protein levels of tissue inhibitor of metalloproteinases-1/2 and E-cadherin. Rescue experiments proved that CTAB induced mesenchymal-epithelial transition in Mahlavu cells and this was significantly dose-dependently mitigated by basic FGF. CONCLUSION: CTAB suppressed the migration and invasion of Mahlavu cells through inhibition of the FGF signaling pathway. CTAB seems to be a potential agent for preventing metastasis of hepatic cancer.


Assuntos
Antineoplásicos/farmacologia , Cetrimônio/farmacologia , Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Anticancer Res ; 40(9): 4913-4919, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878779

RESUMO

BACKGROUND/AIM: A new class of imidazo[2,1-b][1,3,4]thiadiazole compounds have recently been evaluated as inhibitors of phosphorylation of focal adhesion kinase (FAK) in pancreatic cancer. FAK is overexpressed in mesothelioma and has recently emerged as an interesting target for the treatment of this disease. MATERIALS AND METHODS: Ten imidazo[2,1-b][1,3,4]thiadiazole compounds characterized by indole bicycle and a thiophene ring, were evaluated for their cytotoxic activity in two primary cell cultures of peritoneal mesothelioma, MesoII and STO cells. RESULTS: Compounds 1a and 1b showed promising antitumor activity with IC50 values in the range of 0.59 to 2.81 µM in both cell lines growing as monolayers or as spheroids. Their antiproliferative and antimigratory activity was associated with inhibition of phospho-FAK, as detected by a specific ELISA assay in STO cells. Interestingly, these compounds potentiated the antiproliferative activity of gemcitabine, and these results might be explained by the increase in the mRNA expression of the key gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT-1). CONCLUSION: These promising results support further studies on new imidazo[2,1-b][1,3,4]thiadiazole compounds as well as on the role of both FAK and hENT-1 modulation in order to develop new drug combinations for peritoneal mesothelioma.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Transportador Equilibrativo 1 de Nucleosídeo/genética , Quinase 1 de Adesão Focal/metabolismo , Imidazóis/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Estrutura Molecular , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Fosforilação/efeitos dos fármacos , Tiadiazóis/síntese química , Tiadiazóis/química , Células Tumorais Cultivadas
9.
Anticancer Res ; 40(9): 4989-4999, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878787

RESUMO

BACKGROUND/AIM: Epithelial to mesenchymal transition (EMT) is a cellular process that facilitates cancer metastasis. Therefore, therapeutic approaches that target EMT have garnered increasing attention. The present study aimed to examine the in vitro effects of ephemeranthol A on cell death, migration, and EMT of lung cancer cells. MATERIALS AND METHODS: Ephemeranthol A was isolated from Dendrobium infundibulum. Non-small cell lung cancer cells H460 were treated with ephemeranthol A and apoptosis was evaluated by Hoechst 33342 staining. Anoikis resistance was determined by soft agar assay. Wound healing assay was performed to test the migration. The regulatory proteins of apoptosis and cell motility were determined by western blot. RESULTS: Treatment with ephemeranthol A resulted in a concentration-dependent cell apoptosis. At non-toxic concentrations, the compound could inhibit anchorage-independent growth of the cancer cells, as indicated by the decreased colony size and number. Ephemeranthol A also exhibited an inhibitory effect on migration. We further found that ephemeranthol A exerts its antimetastatic effects via inhibition of EMT, as indicated by the markedly decrease of N-cadherin, vimentin, and Slug. Furthermore, the compound suppressed the activation of focal adhesion kinase (FAK) and protein kinase B (Akt) proteins, which are key regulators of cell migration. As for the anticancer activity, ephemeranthol A induced apoptosis by decreasing Bcl-2 followed by the activation of caspase 3 and caspase 9. CONCLUSION: The pro-apoptotic and anti-migratory effects of ephemeranthol A on human lung cancer cells support its use for the development of novel anticancer therapies.


Assuntos
Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Quinase 1 de Adesão Focal/metabolismo , Neoplasias Pulmonares/patologia , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dendrobium/química , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Estrutura Molecular , Fenantrenos/química
10.
Nat Commun ; 11(1): 4498, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908142

RESUMO

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy.


Assuntos
Macrófagos/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Idoso , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/farmacologia , Anilidas/uso terapêutico , Biópsia , Buffy Coat/citologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimioterapia Adjuvante , Técnicas de Cocultura , Intervalo Livre de Doença , Humanos , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Intervalo Livre de Progressão , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/terapia , Procedimentos Cirúrgicos Robóticos , Transdução de Sinais/imunologia , Análise de Célula Única , Células THP-1 , Compostos de Tosil/farmacologia , Compostos de Tosil/uso terapêutico
11.
Int J Nanomedicine ; 15: 6451-6468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922011

RESUMO

Background: Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse. Purpose: The objective of this study was to construct a novel CPP (mmp) modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG2000-MAL and CPP-PVGLIG-PEG5000, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration. Methods and Results: The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP (mmp) modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP (mmp) modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency. Conclusion: CPP (mmp) modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Microambiente Tumoral , Células A549 , Animais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Galinhas , Endocitose/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Hidrólise , Lipossomos , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Microambiente Tumoral/efeitos dos fármacos , Vinorelbina/farmacologia , Vinorelbina/uso terapêutico
12.
Ecotoxicol Environ Saf ; 205: 111312, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956863

RESUMO

Chlorpyrifos (CPF) is one of the most frequently used pesticide in extensive agriculture around the world and can be incorporated by humans and animals with possible consequences on health. The effects of this pesticide on carcinogenesis are not clear and there is no consensus concerning the risks of this compound. In previous work, we demonstrated that CPF induces proliferation of breast cancer cells both in vivo and in vitro. In this work we investigate whether CPF promotes the epithelial-mesenchymal transition (EMT) in breast cancer cells. Herein, we demonstrate that 50 µM CFP induces invasion in MCF-7 and MDA-MB-231 cells. In addition, 0.05 and 50 µM CPF increases migration in both cell lines. In MCF-7 cells, 0.05 and 50 µM CPF increase the metalloprotease MMP2 expression and decrease E-Cadherin and ß-Catenin expression diminishing their membrane location. Furthermore, 50 µM CPF induces Vimentin expression and Slug nuclear translocation in MCF-7 cells. 0.05 and 50 µM CPF increase MMP2 gelatinolytic activity and expression, decrease ß-Catenin expression and increase Vimentin expression in MDA-MB-231 cells. Inhibition of the oncoprotein c-Src reverses all the effects induced by CPF in MDA-MB-231 but not in MCF-7 indicating that c-Src is a kinase with a crucial role in the cells which grow in an estrogen-independent way. In MCF-7 cells both c-Src and estrogen receptor alpha must be blocked to completly inhibit the CPF-mediated effects. Our results show for the first time that the exposure to subthreshold concentrations of CPF promotes the modulation of EMT-molecular markers and pathways. These results, together with the ubiquitous distribution of the pesticide CPF, make it of utmost importance to take measures to minimize the risk of exposure to this compound.


Assuntos
Movimento Celular/efeitos dos fármacos , Clorpirifos/toxicidade , Disruptores Endócrinos/toxicidade , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Praguicidas/toxicidade , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteína Tirosina Quinase CSK/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Relação Dose-Resposta a Droga , Transição Epitelial-Mesenquimal/genética , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Células MCF-7 , Metaloproteinase 2 da Matriz/genética , Transdução de Sinais
13.
PLoS One ; 15(8): e0227157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817719

RESUMO

In mice, experimental influenza virus infection stimulates CD8 T cell infiltration of the airways. Virus is cleared by day 9, and between days 8 and 9 there is an abrupt change in CD8 T cell motility behavior transitioning from low velocity and high confinement on day 8, to high velocity with continued high confinement on day 9. We hypothesized that loss of virus and/or antigen signals in the context of high chemokine levels drives the T cells into a rapid surveillance mode. Virus infection induces chemokine production, which may change when the virus is cleared. We therefore sought to examine this period of rapid changes to the T cell environment in the tissue and seek evidence on the roles of peptide-MHC and chemokine receptor interactions. Experiments were performed to block G protein coupled receptor (GPCR) signaling with Pertussis toxin (Ptx). Ptx treatment generally reduced cell velocities and mildly increased confinement suggesting chemokine mediated arrest (velocity <2 µm/min) (Friedman RS, 2005), except on day 8 when velocity increased and confinement was relieved. Blocking specific peptide-MHC with monoclonal antibody unexpectedly decreased velocities on days 7 through 9, suggesting TCR/peptide-MHC interactions promote cell mobility in the tissue. Together, these results suggest the T cells are engaged with antigen bearing and chemokine producing cells that affect motility in ways that vary with the day after infection. The increase in velocities on day 9 were reversed by addition of specific peptide, consistent with the idea that antigen signals become limiting on day 9 compared to earlier time points. Thus, antigen and chemokine signals act to alternately promote and restrict CD8 T cell motility until the point of virus clearance, suggesting the switch in motility behavior on day 9 may be due to a combination of limiting antigen in the presence of high chemokine signals as the virus is cleared.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Movimento Celular/fisiologia , Vírus da Influenza A/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/fisiologia , Movimento Celular/efeitos dos fármacos , Quimiocinas/imunologia , Vírus da Influenza A/patogenicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae , Infecções por Orthomyxoviridae/imunologia , Toxina Pertussis/metabolismo , Toxina Pertussis/farmacologia , Receptores de Quimiocinas , Receptores Acoplados a Proteínas-G/metabolismo
14.
Gene ; 762: 145044, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32777528

RESUMO

OBJECTIVE: Gastric cancer is the most common malignant tumor. Most patients suffering from gastric cancer die of metastasis. The role of Atrial natriuretic peptide (ANP) in inhibiting and eliminating kinds of cancer cells has been reported. Aberrant activation of Hedgehog (Hh) signaling pathway contributes to initiation and progression of various malignancies. We have previously reported that the inhibitor of Hh, cyclopamine, reduces the metastatic activity of MGC-803 via inhibiting the expression of matrix metalloproteinases (MMP)-9. It remains to be further demonstrated that ANP has the suppressive effects on invasion and metastasis in gastric cancer via Hh-mediated MMP-9 production. METHODS: Transwell, western blot, qRT-PCR were used after application of ANP on MGC-803 gastric cancer cells to determine the levels of cell migration and invasion, protein levels of MMP-9 and Hh, as well as mRNAs of MMP-9 and Hh, respectively. RESULTS: It was demonstrated that the migration and invasion were significantly lower, MMP-9 and Hh as well as their mRNAs were lower as well, in ANP-treated MGC-803 gastric cancer cells than those in control. CONCLUSIONS: The expression of MMP-9 induced by aberrant activation of Hh in MGC-803 was inhibited by ANP, which may contribute to the inhibition of cell migration and invasion. These results suggested the potential of ANP to be used in gastric cancer therapy as an inhibitor targetting Hh signaling pathway to inhibit the proliferation as well as invasion and metastasis of gastric cancer.


Assuntos
Fator Natriurético Atrial/farmacologia , Proteínas Hedgehog/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proteínas Hedgehog/genética , Humanos , Metaloproteinase 9 da Matriz/genética , Transdução de Sinais/efeitos dos fármacos
15.
PLoS One ; 15(8): e0237889, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817625

RESUMO

Tenascin-C (TNC) is an extracellular matrix (ECM) glycoprotein that plays an important role in cell proliferation, migration, and tumour invasion in various cancers. TNC is one of the main protein overexpressed in breast cancer, indicating a role for this ECM molecule in cancer pathology. In this study we have evaluated the TNC loss-off-function in breast cancer cells. In our approach, we used dsRNA sharing sequence homology with TNC mRNA, called ATN-RNA. We present the data showing the effects of ATN-RNA in MDA-MB-231 cells both in monolayer and three-dimensional culture. Cells treated with ATN-RNA were analyzed for phenotypic alterations in proliferation, migration, adhesion, cell cycle, multi-caspase activation and the involvement in epithelial to mesenchymal transition (EMT) processes. As complementary analysis the oncogenomic portals were used to assess the clinical implication of TNC expression on breast cancer patient's survival, showing the TNC overexpression associated with a poor survival outcome. Our approach applied first in brain tumors and then in breast cancer cell lines reveals that ATN-RNA significantly diminishes the cell proliferation, migration and additionally, reverses the mesenchymal cells phenotype to the epithelial one. Thus, TNC could be considered as the universal target in different types of tumors, where TNC overexpression is associated with poor prognosis.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , RNA de Cadeia Dupla/genética , Tenascina/genética , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , RNA de Cadeia Dupla/farmacologia , Tenascina/antagonistas & inibidores
16.
PLoS One ; 15(8): e0236594, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760073

RESUMO

Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity.


Assuntos
Anestésicos/farmacologia , Moduladores GABAérgicos/farmacologia , Ketamina/farmacologia , Microglia/efeitos dos fármacos , Pentobarbital/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tiopental/farmacologia , Xilazina/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos
17.
Chem Biol Interact ; 330: 109232, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32860822

RESUMO

Currently, whether nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation contributes to neuropathy induced by 2,5-Hexanedione (HD), the toxic metabolite of n-hexane, remains unknown. In this study, we found that HD intoxication elevated NLRP3 expression, caspase-1 activation and interleukin-1ß production in sciatic nerve of rats, indicating activation of NLRP3 inflammasome. The increased cleavage of gasdermin D (GSDMD) protein, an important mediator of pyroptosis, and axon degeneration were also observed in sciatic nerves of HD-intoxicated rats. Interestingly, glybenclamide, a widely used inhibitor of NLRP3 inflammasome, significantly reduced NLRP3 inflammasome activation, which was associated with decreased GSDMD cleavage and axon degeneration as well as improved motor performance of HD-intoxicated rats. Subsequently, we found that inhibition of NLRP3 inflammasome by glybenclamide attenuated macrophage infiltration, activation and M1 polarization in sciatic nerves of HD-intoxicated rats. Furthermore, decreased malondialdehyde (MDA) contents and increased glutathione (GSH) level and total anti-oxidative capacity were also observed in sciatic nerves of rats treated with combined glybenclamide and HD compared with HD alone group. Altogether, our findings suggest that NLRP3 inflammasome activation contributes to HD-induced neurotoxicity by enhancing macrophage infiltration and activation as well as oxidative stress, providing a novel mechanism of neuropathy induced by this neurotoxicant.


Assuntos
Hexanonas/toxicidade , Macrófagos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/farmacologia , Síndromes Neurotóxicas/etiologia , Animais , Antioxidantes/metabolismo , Movimento Celular/efeitos dos fármacos , Glutationa/metabolismo , Glibureto/farmacologia , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Síndromes Neurotóxicas/tratamento farmacológico , Estresse Oxidativo , Proteínas de Ligação a Fosfato/metabolismo , Piroptose , Ratos , Nervo Isquiático/metabolismo , Nervo Isquiático/patologia
18.
Int J Nanomedicine ; 15: 5131-5146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764941

RESUMO

Background: Gene therapy is considered a novel way to treat osteosarcoma, and microRNAs are potential therapeutic targets for osteosarcoma. miR-214 has been found to promote osteosarcoma aggression and metastasis. Graphene oxide (GO) is widely used for gene delivery for the distinct physiochemical properties and minimal cytotoxicity. Methods: Polyethyleneimine (PEI)-functionalized GO complex was well-prepared and loaded with miR-214 inhibitor at different concentrations. The load efficacy was tested by gel retardation assay and the cy3-labeled fluorescence of cellular uptake. The experiments of wound healing, immunofluorescence staining, Western blot, qRT-PCR and immunohistochemical staining were performed to measure the inhibitory effect of the miR-214 inhibitor systematically released from the complexes against MG63, U2OS cells and xenograft tumors. Results: The systematic mechanistic elucidation of the efficient delivery of the miR-214 inhibitor by GO-PEI indicated that the inhibition of cellular miR-214 caused a decrease in osteosarcoma cell invasion and migration and an increase in apoptosis by targeting phosphatase and tensin homolog (PTEN). The synergistic combination of the GO-PEI-miR-214 inhibitor and CDDP chemotherapy showed significant cell death. In a xenograft mouse model, the GO-PEI-miR-214 inhibitor significantly inhibited tumor volume growth. Conclusion: This study indicates the potential of functionalized GO-PEI as a vehicle for miRNA inhibitor delivery to treat osteosarcoma with low toxicity and miR-214 can be a good target for osteosarcoma therapy.


Assuntos
Grafite/química , MicroRNAs/antagonistas & inibidores , Terapia de Alvo Molecular , Osteossarcoma/tratamento farmacológico , PTEN Fosfo-Hidrolase/metabolismo , Polietilenoimina/química , Polietilenoimina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Ósseas/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/genética , Terapia Combinada , Humanos , Camundongos , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia
19.
PLoS One ; 15(8): e0237442, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790767

RESUMO

BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among adult males globally. The poor prognosis of PCa is largely due to late diagnosis of the disease when it has already progressed to an advanced stage marked by androgen-independence, thus necessitating new strategies for early detection and treatment. We construe that these direly needed advances are limited by our poor understanding of early events in the progression of PCa and that would thus represent ideal targets for early intervention. To begin to fill this void, we interrogated molecular "oncophenotypes" that embody the transition of PCa from an androgen-dependent (AD) to-independent (AI) state. METHODS: To accomplish this aim, we used our previously established AD and AI murine PCa cell lines, PLum-AD and PLum-AI, respectively, which recapitulate primary and progressive PCa morphologically and molecularly. We statistically surveyed global gene expressions in these cell lines by microarray analysis. Differential profiles were functionally interrogated by pathways, gene set enrichment and topological gene network analyses. RESULTS: Gene expression analysis of PLum-AD and PLum-AI transcriptomes (n = 3 each), revealed 723 differentially expressed genes (392 upregulated and 331 downregulated) in PLum-AI compared to PLum-AD cells. Gene set analysis demonstrated enrichment of biological functions and pathways in PLum-AI cells that are central to tumor aggressiveness including cell migration and invasion facilitated by epithelial-to-mesenchymal transition (EMT). Further analysis demonstrated that the p38 mitogen-activated protein kinase (MAPK) was predicted to be significantly activated in the PLum-AI cells, whereas gene sets previously associated with favorable response to the p38 inhibitor SB203580 were attenuated (i.e., inversely enriched) in the PLum-AI cells, suggesting that these aggressive cells may be therapeutically vulnerable to p38 inhibition. Gene set and gene-network analysis also alluded to activation of other signaling networks particularly those associated with enhanced EMT, inflammation and immune function/response including, but not limited to Tnf, IL-6, Mmp 2, Ctgf, and Ptges. Accordingly, we chose SB203580 and IL-6 to validate their effect on PLum-AD and PLum-AI. Some of the common genes identified in the gene-network analysis were validated at the molecular and functional level. Additionally, the vulnerability to SB203580 and the effect of IL-6 were also validated on the stem/progenitor cell population using the sphere formation assay. CONCLUSIONS: In summary, our study highlights pathways associated with an augmented malignant phenotype in AI cells and presents new high-potential targets to constrain the aggressive malignancy seen in the castration-resistant PCa.


Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Interleucina-6/farmacologia , Neoplasias da Próstata/patologia , Piridinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Imidazóis/uso terapêutico , Interleucina-6/uso terapêutico , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Piridinas/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
PLoS One ; 15(8): e0237025, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797057

RESUMO

Troxerutin (TRX) is a water-soluble flavonoid which occurs commonly in the edible plants. Recent studies state that TRX improves the functionality of the nervous system and neutralizes Amyloid-ß induced neuronal toxicity. In this study, an in vitro assay based upon Neural stem cell (NSCs) isolated from the subventricular zone of the postnatal balb/c mice was established to explore the impact of TRX on individual neurogenesis processes in general and neuroprotective effect against ß-amyloid 1-42 (Aß42) induced inhibition in differentiation in particular. NSCs were identified exploiting immunostaining of the NSCs markers. Neurosphere clonogenic assay and BrdU/Ki67 immunostaining were employed to unravel the impact of TRX on proliferation. Differentiation experiments were carried out for a time span lasting from 48 h to 7 days utilizing ß-tubulin III and GFAP as neuronal and astrocyte marker respectively. Protective effects of TRX on Aß42 induced depression of NSCs differentiation were determined after 48 h of application. A neurosphere migration assay was carried out for 24 h in the presence and absence of TRX. Interestingly, TRX enhanced neuronal differentiation of NSCs in a dose-dependent manner after 48 h and 7 days of incubation and significantly enhanced neurite growth. A higher concentration of TRX also neutralized the inhibitory effects of Aß42 on neurite outgrowth and length after 48 h of incubation. TRX significantly stimulated cell migration. Overall, TRX not only promoted NSCs differentiation and migration but also neutralized the inhibitory effects of Aß42 on NSCs. TRX, therefore, offers an interesting lead structure from the perspective of drug design especially to promote neurogenesis in neurological disorders i.e. Alzheimer's disease.


Assuntos
Hidroxietilrutosídeo/análogos & derivados , Neuritos/efeitos dos fármacos , Crescimento Neuronal/fisiologia , Precursor de Proteína beta-Amiloide/farmacologia , Animais , Astrócitos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Flavonoides/farmacologia , Hidroxietilrutosídeo/metabolismo , Hidroxietilrutosídeo/farmacologia , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese , Neurônios/metabolismo , Neuroproteção , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA