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1.
Oncol Rep ; 44(3): 1049-1063, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32705271

RESUMO

Increasing evidence indicates that the inflammatory tumor microenvironment can lead to cancer cell metastasis. Shikonin, which is extracted from the Chinese herb Zicao (the dried root of Lithospermum erythrorhizon), possesses various pharmacological effects, but its effect on tumor metastasis in the inflammatory microenvironment remains unknown. In the present study, we aimed to investigate the potential effect of shikonin on tumor metastasis in an inflammatory microenvironment as well as the underlying molecular mechanisms. It was found that, in the inflammatory microenvironment simulated by THP­1 cell conditioned medium (THP­1­CM) in vitro, shikonin significantly inhibited the epithelial­mesenchymal transition (EMT), migration and invasion of human lung adenocarcinoma cell lines A549 and H1299. In addition, we found that interleukin­6 (IL­6), which is expressed in THP­1­CM, promoted the EMT of lung adenocarcinoma cells, and shikonin markedly inhibited IL­6­induced EMT and cell motility. Moreover, shikonin inhibited IL­6­induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), prevented phosphorylated STAT3 (p­STAT3) translocation into the nucleus, and suppressed p­STAT3 transactivation activity. Additionally, it was found that shikonin inhibited lung metastasis, EMT and expression of p­STAT3 of A549 cells in vivo. Furthermore, IL­6 levels in human lung adenocarcinoma tissues were significantly associated with tumor­node­metastasis stage and lymph node metastasis, and its expression was correlated with tumor­associated macrophage (TAM) infiltration. Together, these results suggest that shikonin suppresses the migration and invasion of human lung adenocarcinoma cells in an inflammatory microenvironment involving the IL­6/STAT3 signaling pathway.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Metástase Linfática/tratamento farmacológico , Naftoquinonas/farmacologia , Células A549 , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/secundário , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/imunologia , Feminino , Humanos , Interleucina-6/análise , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Metástase Linfática/imunologia , Masculino , Pessoa de Meia-Idade , Naftoquinonas/uso terapêutico , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/prevenção & controle , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Int Immunopharmacol ; 78: 106064, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31838448

RESUMO

Transforming growth factor (TGF)-ß/Smad signalling plays a central role in the pathogenesis of peritoneal fibrosis related to peritoneal dialysis (PD). Parthenolide (PTL), a naturally occurring phytochemical, is isolated from the shoots of feverfew (Tanacetum parthenium) and displays analgesia, anti-inflammation and anticancer activities. In this study, we examined the therapeutic potential of PTL on PD-related peritoneal fibrosis induced by daily intraperitoneal injection of 4.25% dextrose-containing PD fluid (PDF) in vivo and TGF-ß1-induced epithelial-mesenchymal transition (EMT) in vitro. PTL was administered daily before PDF injection or after 14 days of PDF injection. Both PTL treatments showed a protective effect on peritoneal fibrosis and prevented peritoneal dysfunction. Similarly, PTL suppressed the expression of fibrotic markers (fibronectin and collagen I) and restored the expression of the epithelial marker (E-cadherin) in TGF-ß1-treated HMrSV5 cells. Furthermore, PTL inhibited TGF-ß1-induced Smad2 and Smad3 phosphorylation and nuclear translocation but did not influence Smad1/5/9 phosphorylation or activate other downstream signalling pathways of TGF-ß1, including AKT, extracellular signal-regulated kinase (ERK) or p38. In conclusion, PTL treatment may represent an effective and novel therapy for PD-associated peritoneal fibrosis by suppressing the TGF-ß/Smad pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/tratamento farmacológico , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Linhagem Celular , Soluções para Diálise/administração & dosagem , Soluções para Diálise/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/imunologia , Feminino , Humanos , Masculino , Camundongos , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/imunologia , Fibrose Peritoneal/patologia , Peritônio/citologia , Peritônio/efeitos dos fármacos , Peritônio/imunologia , Peritônio/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/imunologia , Sesquiterpenos/uso terapêutico , Transdução de Sinais/imunologia , Proteínas Smad/imunologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismo
3.
Toxicol Lett ; 265: 9-16, 2017 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-27866977

RESUMO

Qing Ye Dan (QYD) is the whole plant of Swertia mileensis and used in Chinese folk medicine for the treatment of prostatitis, benign prostatic hyperplasia (BPH) and so on. This study was to investigate the effects of QYD and its main component swertiamarin on BPH induced by testosterone in rats. The prostatic expressions of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (ßFGF) and proliferating cell nuclear antigen (PCNA) were detected by immunohistochemistry assay. Prostatic levels of oxidative stress and inflammatory-related factors were also analyzed. Additionally, the prostatic expressions of androgen receptor (AR), estrogen receptor (ER)-α, ER-ß, hypoxia-inducible factor (HIF)-1α, B-cell CLL/lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax) were measured by western blot. The epithelial-mesenchymal transition (EMT) associated factors were evaluated by quantitative RT-PCR. It showed that QYD and swertiamarin ameliorated the testosterone-induced prostatic hyperplasia and collagen deposition, attenuated the over-expressions of HIF-1α, VEGF, EGF, ßFGF, PCNA, AR and ER-α, reduced the ratio of Bcl-2/Bax, enhanced the expression of ER-ß, inhibited the oxidative stress and local inflammation, as well as relieved prostatic EMT. It suggested that QYD and swertiamarin had prostatic protective potential against BPH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucosídeos Iridoides/uso terapêutico , Hiperplasia Prostática/prevenção & controle , Pironas/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/toxicidade , Antioxidantes/administração & dosagem , Antioxidantes/isolamento & purificação , Antioxidantes/toxicidade , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/toxicidade , Transição Epitelial-Mesenquimal/imunologia , Feminino , Glucosídeos Iridoides/administração & dosagem , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/toxicidade , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Próstata/efeitos dos fármacos , Próstata/imunologia , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Pironas/administração & dosagem , Pironas/isolamento & purificação , Pironas/toxicidade , Ratos Wistar , Swertia/química , Testosterona/administração & dosagem , Testosterona/farmacologia , Testes de Toxicidade
4.
Oncol Rep ; 34(5): 2445-50, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26324883

RESUMO

Epithelial-mesenchymal transition (EMT) is a pivotal event in the invasion and metastasis of cancer cells. Prunella vulgaris (PV) inhibits the proliferation of various cancer cells; however, its possible role in EMT has not been demonstrated. In the present study, we explored the effect of PV aqueous extract (PVAE), a typical medicine for decoction, on EMT. Lipopolysaccharide (LPS) induced EMT-like phenotype changes in cancer cell lines that enhanced cell migration and invasion. PVAE markedly inhibited these effects and produced accompanying changes in the expression of EMT markers, including decreased expression of N-cadherin and vimentin, and increased expression of ß-catenin. We found that PVAE effects on LPS-induced EMT were mediated by inhibition of the NF-κB/Snail signaling pathway. Our findings provide new evidence that PVAE suppresses cancer invasion and migration by inhibiting EMT. Therefore, we suggest that PVAE is an effective dietary chemopreventive agent with antimetastatic activity against malignant tumors.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Transição Epitelial-Mesenquimal/imunologia , Lipopolissacarídeos/farmacologia , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , NF-kappa B/metabolismo , Invasividade Neoplásica , Extratos Vegetais/isolamento & purificação , Prunella/química , Fatores de Transcrição da Família Snail , Solventes/química , Fatores de Transcrição/metabolismo , Água/química
5.
Artigo em Inglês | MEDLINE | ID: mdl-24383438

RESUMO

Airway and pulmonary fibrosis is a pathological condition associated with chronic airway inflammation. Fibrosis and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The traditional paradigm of fibrogenesis is based on the activation of local stromal cells including fibroblasts and their conversion into myofibroblasts. However, it has become apparent that several airway structural cells, including epithelial cells, endothelial cells, and pericytes, contribute to lung fibrosis through a process of molecular reprogramming. Recent studies have shown the important role of epithelial-mesenchymal transition (EMT) in airway diseases and animal models of fibrosis, suggesting that targeting EMT may be a promising strategy against fibrotic lung disease. In this article, we review the latest advances on the evidence for EMT in airway diseases, and discuss the underlying mechanisms of EMT and the roles of inflammatory mediators. We also describe recent patents that could develop into novel therapeutics.


Assuntos
Mediadores da Inflamação/metabolismo , Pneumopatias/terapia , Pulmão/patologia , Miofibroblastos/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Mucosa Respiratória/imunologia , Células Estromais/patologia , Fator de Crescimento Transformador beta/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Remodelação das Vias Aéreas/imunologia , Animais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/imunologia , Fibrose , Humanos , Niacinamida/uso terapêutico , Patentes como Assunto , Mucosa Respiratória/fisiopatologia , Sorafenibe
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