Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
iScience ; 21: 549-561, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31715498

RESUMO

Multi-targeted kinase inhibitors, such as sorafenib, have been used in various malignancies, but their efficacy in clinical applications varies among individuals and lacks pretherapeutic prediction measures. We applied the concept of "click chemistry" to pathological staining and established a drug-loaded probe staining assay. We stained the cells and different types of pathological sections and demonstrated that the assay was reliable. We further verified in cells, cell-derived xenograft model, and clinical level that the staining intensity of the probe could reflect drug sensitivity. The stained samples from 300 patients who suffered from hepatocellular carcinoma and used the sorafenib probe also indicated that staining intensity was closely related to clinical information and could be used as an independent marker without undergoing sorafenib therapy for prognosis. This assay provided new ideas for multi-target drug clinical trials, pre-medication prediction, and pathological research.

2.
Cancer Res ; 79(7): 1451-1464, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30760518

RESUMO

Quaking (QKI) is an alternative splicing factor that can regulate circRNA formation in the progression of epithelial-mesenchymal transition, but the mechanism remains unclear. High expression of QKI is correlated with short survival time, metastasis, and high clinical stage and pathology grade in hepatocellular carcinoma (HCC). Here we report that transcription of the QKI gene was activated by the Yin-Yang 1 (YY1)/p65/p300 complex, in which YY1 bound to the super-enhancer and promoter of QKI, p65 combined with the promoter, and p300 served as a mediator to maintain the stability of the complex. This YY1/p65/p300 complex increased QKI expression to promote the malignancy of HCC as well as an increased circRNA formation in vitro and in vivo. Hyperoside is one of several plant-derived flavonol glycoside compounds. Through virtual screening and antitumor activity analysis, we found that hyperoside inhibited QKI expression by targeting the YY1/p65/p300 complex. Overall, our study suggests that the regulatory mechanism of QKI depends on the YY1/p65/p300 complex and that it may serve as a potential target for treatment of HCC. SIGNIFICANCE: These findings identify the YY1/p65/p300 complex as a regulator of QKI expression, identifying several potential therapeutic targets for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Elementos Facilitadores Genéticos , Transição Epitelial-Mesenquimal , Neoplasias Hepáticas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica/prevenção & controle , Regiões Promotoras Genéticas , Biossíntese de Proteínas , Quercetina/análogos & derivados , Quercetina/farmacologia , Proteínas de Ligação a RNA/genética , Transcrição Genética
3.
Eur Spine J ; 28(3): 492-501, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30656471

RESUMO

PURPOSE: Ossification of ligamentum flavum (OLF) is the leading cause of progressive thoracic myelopathy (TM) in East Asian countries. Surgical decompression is the general treatment for TM. This study investigated the application of percutaneous full endoscopic posterior decompression (PEPD) for the treatment of thoracic OLF. METHODS: Eighteen patients with TM were treated by PEPD under local anaesthesia. Patients had an average age of 59.1 years and single-level lesions mostly at the lower thoracic vertebrae. Computed tomography and magnetic resonance imaging were used to classify the OLF. The pre- and postoperative neurological statuses were evaluated using the American Spinal Injury Association (ASIA) sensory and motor score, modified Japanese Orthopaedic Association (mJOA) score and Frankel grade. RESULTS: OLF for all patients was classed as lateral, extended, and enlarged types without comma and tram track signs. Decompression was completed, and a dome-shaped laminotomy was performed through limited laminectomy and flavectomy. Dural tears in 2 patients were the only observed complication. The average score of ASIA sensory and motor, mJOA, as well as the Frankel grade improved significantly after surgery at an average follow-up time of 17.4 months. The average recovery rate (RR) was 47.5% as calculated from the mJOA scores. According to RR, 10 cases were classified as good, 4 cases fair, and 4 cases unchanged. CONCLUSIONS: For patients with thoracic OLF at a single level and lateral, extended, and enlarged types without comma and tram track signs, it is safe and reliable to perform PEPD, which has satisfactory clinical results. These slides can be retrieved under Electronic Supplementary Material.

4.
Oncogene ; 38(2): 228-243, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30087438

RESUMO

Hepatocellular carcinoma (HCC) is a typical hypervascular solid tumor. Vasculogenic mimicry (VM) formed by aggressive tumor cells to mimic vasculogenic networks plays an important role in the tumor malignancy of HCC. Hsp90ß promotes endothelial cell-dependent angiogenesis in HCC. However, the relationship between Hsp90ß and VM formation is unclear. In this study, we found that Hsp90ß is positively correlated with VM and EMT marker proteins in HCC tissues and promotes tube formation, cell migration, and invasion in vitro. Hsp90ß interacts with Twist1 and promotes its deubiquitination and stabilization to nuclear translocation and enhances the VE-cadherin promoter activity. Results of in vitro analysis indicate that Hsp90ß enhances the tumor VM in tumor-burdened mice, and the Hsp90 inhibitor NVP-BEP800 suppresses VM formation by releasing Hsp90ß and Twist1 interaction. This study provides a potential antitumor therapy for inhibiting VM by targeting Hsp90ß in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias Hepáticas/patologia , Animais , Carcinoma Hepatocelular/metabolismo , Xenoenxertos , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica
5.
Toxicol Appl Pharmacol ; 360: 1-8, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30240696

RESUMO

BACKGROUND: Selenium supplementation can be used to treat tumors. However, inorganic selenium is highly toxic, and natural organic selenium is extremely rare. Polysaccharides can improve drug bioavailability and targeting. Lentinan is a polysaccharide that has been approved as an anti-cancer drug in Japan and China. METHODS: Lentinan, an antitumor polysaccharide extracted from Lentinus edodes, was conjugated with seleninic acid to be transformed into ester (Se-lentinan) and utilized as drug carrier. The enhancement of the anti-tumor effects of Se-lentinan was evaluated by cell viability, cell cycle, migration, and transwell assays and animal xenograft models. The effects of Se-lentinan on the expression levels of epithelial-mesenchymal transition (EMT) markers were determined through immunofluorescence, Western blot, and immunohistochemistry analyses. RESULTS: Se-lentinan inhibited the invasiveness of B16-BL6 and HCT-8 cells by suppressing EMT. In vivo, Se-lentinan significantly inhibited tumor growth and metastasis of the transplanted melanoma and colon cancer cells and showed less toxicity than sodium selenite. Moreover, Se-lentinan reduced the accumulation of selenium in the liver and kidney tissues of mice and exhibited low organ toxicity. CONCLUSION: The antitumor activity of selenium was enhanced greatly, and its side effects were reduced with the use of lentinan as drug carrier.


Assuntos
Antineoplásicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lentinano/farmacologia , Selênio/farmacologia , Células A549 , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Células HEK293 , Humanos , Células MCF-7 , Melanoma Experimental/tratamento farmacológico , Camundongos , Células NIH 3T3 , Metástase Neoplásica/tratamento farmacológico , Polissacarídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Exp Clin Cancer Res ; 37(1): 185, 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30081924

RESUMO

BACKGROUND: Tumor cells transfer into endothelial cells by epithelial-endothelial transition (EET), which is characterized by vasculagenic mimicry (VM) in morphology. VM can change tumor microcirculation, progression, and metastasis. However, the molecular mechanisms of endothelial-like transition remain unclear. EET is a subtype of epithelial-mesenchymal transition (EMT). Twist1, a transcriptional regulatory factor of EMT, is an important factor that induces EET in hepatocellular carcinoma(HCC), but the upstream signal of Twist1 is unclear. METHODS: Expression plasmids, Ca mobilization, and three-dimensional cultures were evaluated. Western blot assay, reporter gene assay, and immunofluorescence staining were conducted. A murine xenograft model was established. Analyses of immunohistochemistry, patient samples, and complementary DNA (cDNA) microarrays were also performed. RESULTS: This study demonstrated that protease-activated receptor-1 (PAR1) can increase the expression of endothelial markers and enhance VM formation by upregulating Twist1 both in vitro and in vivo through thrombin binding. Thrombin not only activates PAR1 but also promotes PAR1 internalization in a time-dependent manner. Clinical pathological analysis further confirms that PAR1 expression is directly correlated with the endothelial marker expression, VM formation, and metastasis and indicates poor survival rate of patients with tumors. CONCLUSION: PAR1 promotes EET through Twist1 in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Nucleares/metabolismo , Receptor PAR-1/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Células Hep G2 , Xenoenxertos , Humanos , Neoplasias Hepáticas/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Nucleares/genética , Receptor PAR-1/biossíntese , Receptor PAR-1/genética , Proteína 1 Relacionada a Twist/genética
7.
Respir Res ; 19(1): 111, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29871641

RESUMO

BACKGROUND: Parthenolide (PTL) is a natural molecule isolated from Tanacetum parthenium that exhibits excellent anti-inflammatory and antitumor activities. Pulmonary fibrosis (PF), especially idiopathic pulmonary fibrosis (IPF), is a chronic lung disease that lacks a proven effective therapy. The present study evaluated the therapeutic effect of PTL on PF. METHODS: Serum-starved primary lung fibroblasts and HFL1 cells were treated with different doses of PTL, and cell viability and the migration rate were measured. Western blot analysis and a dual-luciferase assay were used to analyze the epithelial-mesenchymal transition (EMT)-related transcription factors influenced by PTL treatment in A549 cells and primary lung epithelial cells. Mice with bleomycin (BLM)-induced pulmonary fibrosis were treated with different doses of intragastric PTL, and pathological changes were evaluated using Hematoxylin-eosin (H&E) staining and immunohistochemical analysis. RESULTS: Our results demonstrated that PTL reduced the cell viability and migration rate of lung fibroblasts and inhibited the expression of EMT-related transcription factors in lung epithelial cells. In vivo studies demonstrated that PTL attenuated BLM-induced pulmonary fibrosis and improved the body weight and pathological changes of BLM-treated mice. We further demonstrated that PTL attenuated BLM-induced PF primarily via inhibition of the NF-κB/Snail signaling pathway. CONCLUSION: These findings suggest that PTL inhibits EMT and attenuates BLM-induced PF via the NF-κB/Snail signaling pathway. PTL is a worthwhile candidate compound for pulmonary fibrosis therapy.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Bleomicina/toxicidade , NF-kappa B/antagonistas & inibidores , Fibrose Pulmonar/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Células A549 , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Sesquiterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Transcrição da Família Snail/metabolismo
8.
Cancer Res ; 78(15): 4150-4162, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29844124

RESUMO

Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of vimentin. How Twist1 regulates this expression remains unclear. Here, we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and to selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 in vitro and in patient-derived xenograft and diethylnitrosamine-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circular RNA (circRNA)-based diagnostic and therapeutic strategies.Significance: A circRNA-based mechanism drives Twist1-mediated regulation of vimentin during EMT and provides potential therapeutic targets for treatment of HCC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4150/F1.large.jpg Cancer Res; 78(15); 4150-62. ©2018 AACR.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas Culina/genética , Transição Epitelial-Mesenquimal/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , RNA/genética , Proteína 1 Relacionada a Twist/genética , Vimentina/genética , Animais , Linhagem Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Humanos , Camundongos , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética
9.
Sci Transl Med ; 10(442)2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29794062

RESUMO

The co-silencing of multiple tumor suppressor genes can lead to escalated malignancy in cancer cells. Given the limited efficacy of anticancer therapies targeting single tumor suppressor genes, we developed small circular single-stranded DNA (CSSD) that can up-regulate the expression of co-silenced tumor suppressor genes by sequestering microRNAs (miRNAs) that negatively regulate these genes. We found that cancer patients with low tumor expression of the tumor suppressor genes KLF17, CDH1, and LASS2 had shortened survival times. The up-regulation of these genes upon transfection of artificial CSSD-9 inhibited tumor proliferation and metastasis and promoted apoptosis in vitro as well as in ex vivo and patient-derived xenograft models. In addition, CSSD is more stable and effective than current miRNA inhibitors, and transfecting CSSDs via nanoparticles substantially improved delivery efficiency. The use of a single CSSD can promote the inhibition of multiple tumor suppressor genes. This study provides evidence for the possibility of using CSSDs as therapeutic miRNA inhibitors to target the co-silencing of multiple tumor suppressor genes.


Assuntos
DNA de Cadeia Simples/metabolismo , Inativação Gênica , Genes Supressores de Tumor , Nanopartículas/química , Neoplasias/genética , Neoplasias/patologia , Antineoplásicos/farmacologia , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , DNA Circular/metabolismo , DNA Circular/ultraestrutura , DNA de Cadeia Simples/ultraestrutura , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Neoplásicos , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , MicroRNAs/genética , MicroRNAs/metabolismo , Nanopartículas/ultraestrutura , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Oncotarget ; 8(59): 100216-100226, 2017 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-29245972

RESUMO

Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. Here, we investigated the effects of apigeninin inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Apigenin effectively inhibited ulcerative colitis, a type of IBD, and CAC. Apigenin decreased myeloperoxidase (MPO), inflammatory cytokine and COX-2 levels, and it attenuated inflammatory cell infiltration in treated colon tissues as compared to untreated model colon tissues. Apigenin also reduced NF-κB and STAT3 activity in vitro and in vivo, thereby inhibiting inflammation and inflammation-induced carcinogenesis. Thus apigenin appears to inhibit inflammation and inflammation-induced carcinogenesisin IBD and CAC by suppressing STAT3-NF-κB signaling.

11.
J Thorac Dis ; 9(11): 4376-4386, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29268507

RESUMO

Background: Paraquat (PQ) is a highly efficient herbicide that remains widely used in agriculture. However, the inappropriate application of this herbicide may cause multiple organ injuries including pulmonary injury. In this study, we report that doxycycline (Doxy) treats PQ-induced pulmonary fibrosis (PF). Methods: Mice with PQ-induced PF were treated with different doses of Doxy by intragastric administration. Human lung cancer cell line A549 pre-treated with TGF-ß1 (5 ng/mL) were treated with Doxy hydrochloride (3.4 µM). Results: PF was observed from day 28 in PQ-treated group and Doxy treatments significantly reduced pulmonary coefficient, histopathological score and collagen content in a dose-dependent manner. Doxy can inhibit the expression levels of plasma inflammation cytokines at day 28 after modeling and reduced inflammatory response at early stage of PQ-induced lung injury. Immunohistochemical staining assay and proteomic analysis indicated that Doxy could restore ectopic epithelial-mesenchymal transition (EMT) induced by PQ-treatment by regulating numerous TGF-ß signaling related proteins. Conclusions: The findings suggest that Doxy can restore the balance of epithelial-mesenchymal cells and attenuate PQ-induced PF by downregulating the TGF-ß signaling pathway.

12.
Oncotarget ; 8(61): 103815-103827, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29262602

RESUMO

Artemisinin and its derivatives exhibit a high activity against a range of cancer cell types both in vitro and in vivo. In clinical practice, platinum-based anti-cancer chemotherapy is widely used to treat tumors. However, a large proportion of patients receiving these treatments will relapse because of metastasis and drug resistance. The purpose of this study is to explore the combinational anti-metastatic effect of platinum-based drugs and dihydroartemisinin (DHA). Both DDP and oxaliplatin (OXA) at low doses could induce epithelial-mesenchymal transition (EMT) in HCC. Meanwhile, co-administration of DHA could enhance DDP and OXA chemosensitivity in HCC and reverse drug resistance. DHA reversed the morphological changes induced by DDP or OXA and reversed the changes in EMT biomarkers induced by DDP and OXA in HCC in vitro and in vivo via AKT-Snail signaling. DHA significantly increased platinum-based drug sensitivity and suppressed EMT induced by platinum-based drugs via AKT-Snail signaling in HCC. DHA is expected to become the new adjuvant for chemotherapy.

13.
Oncotarget ; 8(41): 70192-70203, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050271

RESUMO

Sesquiterpene lactones (SL) have a wide range of applications in anti-tumor and anti-inflammatory therapy. However, the pharmacological mechanism of such substances is not clear. In this study, parthenolide (PTL) was used as an example to explore the anti-tumor effect of natural molecules and their common mechanism. We showed that PTL inhibited the proliferation and migration by reverse EMT via the ERK2/NF-κB/Snail pathway in vivo and in vitro. Interestingly, Multiple potential targets of PTL contain a Gly-Leu-Ser/Lys-"co-adaptation pocket". This inspiring us analogies of PTL may also bind to these target proteins and play a similar function. Significantly, the Concept of co-adaptation pocket may help to increase the selectivity of drug research and development.

14.
Oncotarget ; 8(32): 52901-52912, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28881781

RESUMO

Multidrug resistance is a major problem in colon cancer treatment. However, its molecular mechanisms remain unclear. Recently, the epithelial-mesenchymal transition (EMT) in anticancer drug resistance has attracted increasing attention. This study investigated whether vincristine treatment induces EMT and promotes multidrug resistance in colon cancer. The result showed that vincristine treatment increases the expression of several ATP-binding cassette transporters in invasive human colon adenocarcinoma cell line (HCT-8). Vincristine-resistant HCT-8 cells (HCT-8/V) acquire a mesenchymal phenotype, and thus its migratory and invasive ability are increased both in vitro and in vivo. The master transcriptional factors of EMT, especially Twist1, were significantly increased in the HCT-8/V cell line. Moreover, the ectopic expression of Twist1 increased the chemoresistance of HCT-8 cells to vincristine and increased the expression levels and promoter activities of ABCB1 and ABCC1. Furthermore, Twist1 silencing reverses the EMT phenotype, enhances the chemosensitivity of HCT-8/ V cells to anticancer agents in vitro and in vivo, and downregulates the expression of ABCB1 and ABCC1. Twist1-mediated promotion of ABCB1 and ABCC1 expression levels plays an important role in the drug resistance of colon cancer cells.

15.
Theranostics ; 7(2): 425-435, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28255340

RESUMO

Phenytoin, an antiepileptic drug, has been widely used for wound healing. Inspired by previous studies, phenytoin silver (PnAg), a sparingly soluble silver nanocompound, was synthesized which exhibited good therapeutic efficacy in tissue repair with low toxicity (LD50 >5 g/kg). In vivo studies showed that PnAg could accelerate dermal wound healing and strong inflammation control in Sprague-Dawley rats (SD rat) and Bama minipigs. Due to its low solubility, PnAg led to low toxicity and blood enrichment in animals. Furthermore, PnAg could upregulate the promoter activity of Jak, Stat3, and Stat3 downstream proteins. Therefore, PnAg may serve as an effective therapeutic compound for wound healing through regulating the gp130/Jak/Stat3 signaling pathway.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , Fatores Imunológicos/administração & dosagem , Nanoestruturas/administração & dosagem , Fenitoína/administração & dosagem , Prata/administração & dosagem , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Animais , Receptor gp130 de Citocina/agonistas , Modelos Animais de Doenças , Janus Quinases/metabolismo , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Suínos , Porco Miniatura , Resultado do Tratamento
16.
Oncotarget ; 7(27): 41421-41431, 2016 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-27203387

RESUMO

Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. In this study, we investigated the effects of apigenin on migration and metastasis in experimental human hepatocellular carcinoma (HCC) cell lines in vitro and in vivo. Apigenin dose-dependently inhibited proliferation, migration, and invasion by PLC and Bel-7402 human HCC cells. It also suppressed tumor growth in PLC cell xenografts without altering body weight, thereby prolonging survival. Apigenin reduced Snai1 and NF-κB expression, reversed increases in epithelial-mesenchymal transition (EMT) marker levels, increased cellular adhesion, regulated actin polymerization and cell migration, and inhibited invasion and migration by HCC cells. Apigenin may therefore inhibit EMT by inhibiting the NF-κB/Snail pathway in human HCC.


Assuntos
Apigenina/farmacologia , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Hepáticas/patologia , NF-kappa B/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Transdução de Sinais/efeitos dos fármacos
17.
Oncotarget ; 6(38): 40667-79, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26512779

RESUMO

The gelatinase inhibitor doxycycline is the prototypical antitumor antibiotic. We investigated the effects of doxycycline on the migration, invasion, and metastasis of human lung cancer cell lines and in a mouse model. We also measured the effect of doxycycline on the transcription of epithelial-mesenchymal transition (EMT) markers, and used immunohistochemistry to determine whether EMT reversal was associated with doxycycline inhibition. Doxycycline dose-dependently inhibited proliferation, migration, and invasion of NCI-H446 human small cell lung cancer cells. It also suppressed tumor growth from NCI-H446 and A549 lung cancer cell xenografts without altering body weight, inhibited Lewis lung carcinoma cell migration, and prolonged survival. The activities of the transcription factors Twist1/2, SNAI1/2, AP1, NF-κB, and Stat3 were suppressed by doxycycline, which reversed EMT and inhibited signal transduction, thereby suppressing tumor growth and metastasis. Our data demonstrate functional targeting of transcription factors by doxycycline to reverse EMT and suppress tumor proliferation and metastasis. Thus, doxycycline selectively targets malignant tumors and reduces its metastatic potential with less cytotoxicity in lung cancer patients.


Assuntos
Antibacterianos/farmacologia , Carcinoma Pulmonar de Lewis/prevenção & controle , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Doxiciclina/farmacologia , Neoplasias Pulmonares/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Transição Epitelial-Mesenquimal , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Células Tumorais Cultivadas , Cicatrização/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Chin Med J (Engl) ; 128(19): 2570-6, 2015 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-26415792

RESUMO

BACKGROUND: High intracuff pressure can cause severe pharyngeal complications including sore throat or hoarseness after laryngeal mask airway (LMA) removal postoperatively. Though the application of minimum effective cuff inflating volume is suggested to maintain airway sealing and adequacy of ventilation for patients receiving general anesthesia with LMA at lower level of the intracuff pressure, it is currently not a standard care in most of the anesthetic departments. In this study, the minimum effective cuff inflating volume was determined for classic LMA Well Lead™ (Well Lead Medical Co., Ltd., China) and its impact on postoperative pharyngeal complications was also explored. METHODS: Patients with American Society of Anesthesiologists physical status (I-III) undergoing the short-duration urological surgery were recruited in this trial. First, the minimum effective cuff inflating volume was determined for size 4 or 5 LMA Well Lead in the study 1. Immediately following placement and confirmation of ideal LMA position, the cuff was inflated with 5, 7, 10 ml of air and up to 30 ml at 5 ml increment. The intracuff pressure, oropharyngeal leak pressure (OLP), and inspiratory peak airway pressure under positive pressure ventilation at the corresponding cuff volume as indicated above were recorded. Second, the enrolled patients were randomly allocated into minimum effective cuff inflating volume group (MC) and routine care (RC) group in the study 2. The minimum effective cuff inflating volume was applied and maintained in MC group, whereas the cuff volume was inflated with half of the maximum cuff inflating volume recommended by manufacturer in RC group throughout the surgical procedure and stay in postanesthesia care unit prior to LMA removal. The incidence of pharyngeal complications at 0, 2, 24, and 48 h after removal of LMA and other intra-operative adverse events were also documented. RESULTS: The intracuff pressure varied with the cuff inflating volume in a positive linear correlation manner (Y = 11.68X - 42.1, r(2) = 0.9191) under the range of 5-30 ml for size 4 LMA. In similar with size 4 LMA, the data were also showed the linear relationship between the intracuff pressure and the cuff inflating volume (Y = 7.39X - 10.9, r(2) = 0.8855) for size 5 LMA. The minimal effective cuff inflating volume for size 4 or 5 LMA was 7-9 ml in combination of considering OLP needed to maintain airway sealing during intermittently positive pressure ventilation. The intracuff pressure in MC group was lower compared with RC group (63.0 ± 3.7 vs. 126.4 ± 24.0 cmH2O for size 4 LMA; 55.6 ± 2.4 vs. 138.5± 26.8 cmH2O for size 5 LMA; P < 0.0001). The incidence of pharyngeal adverse events was lower in MC group versus the RC group at 2, 24 h after LMA removal. CONCLUSIONS: The relationship between the cuff inflating volume and the intracuff pressure for size 4 or 5 LMA Well Lead(TM) is in a linear correlation manner at the range of 5-30 ml. The minimal cuff inflating volume is adequate for satisfactory airway sealing and consequently associated with lower incidence of postoperative pharyngeal complications for LMA Well Lead.™.


Assuntos
Máscaras Laríngeas/efeitos adversos , Faringe/cirurgia , Idoso , Feminino , Rouquidão/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Faringite/etiologia , Complicações Pós-Operatórias/etiologia
19.
J Pharmacol Exp Ther ; 353(3): 573-81, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25876909

RESUMO

Partial agonists of peroxisome proliferator-activated receptor γ (PPARγ) reportedly reverse insulin resistance in patients with type 2 diabetes mellitus. In this work, a novel non-thiazolidinedione-partial PPARγ ligand, MDCCCL1636 [N-(4-hydroxyphenethyl)-3-mercapto-2-methylpropanamide], was investigated. The compound displayed partial agonist activity in biochemical and cell-based transactivation assays and reversed insulin resistance. MDCCCL1636 showed a potential antidiabetic effect on an insulin-resistance model of human hepatocarcinoma cells (HepG2). High-fat diet-fed streptozotocin-induced diabetic rats treated with MDCCCL1636 for 56 days displayed reduced fasting serum glucose and reversed dyslipidemia and pancreatic damage without significant weight gain. Furthermore, MDCCCL1636 had lower toxicity in vivo and in vitro than pioglitazone. MDCCCL1636 also potentiated glucose consumption and inhibited the impairment in insulin signaling targets, such as AKT, glycogen synthase kinase 3ß, and glycogen synthase, in HepG2 human hepatoma cells. Overall, our results suggest that MDCCCL1636 is a promising candidate for the prevention and treatment of type 2 diabetes mellitus.


Assuntos
Ácido 3-Mercaptopropiônico/análogos & derivados , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , PPAR gama/agonistas , Fenóis/farmacologia , Ácido 3-Mercaptopropiônico/farmacologia , Animais , Glicemia/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/tratamento farmacológico , Dislipidemias/etiologia , Humanos , Hipoglicemiantes/toxicidade , Pâncreas/patologia , Pioglitazona , Ratos , Ratos Wistar , Tiazolidinedionas/uso terapêutico , Ativação Transcricional/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos , Peixe-Zebra
20.
Bioorg Med Chem Lett ; 24(1): 386-9, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24269122

RESUMO

Captopril is a New Delhi metallo-ß-lactamase-1 (NDM-1) inhibitor with an IC50 value of 7.9µM. It is composed of two units: a 3-mercapto-2-methylpropanoyl fragment and a proline residue. In this study, we synthesized simple amide derivatives of 3-mercapto-2-methylpropanoic acid, and then tested them as NDM-1 inhibitors in order to identify the pharmacophore for NDM-1 inhibition. We found that the lead compound 22 had an IC50 value of 1.0µM. Further structure simplification provided compounds 31 and 32, which had IC50 values of 15 and 10µM, respectively. As compound 32 is a clinically used antidote for metal poisoning, it has great potential to be repurposed to treat bacterial infections.


Assuntos
Captopril/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de beta-Lactamases , Captopril/síntese química , Captopril/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Relação Estrutura-Atividade , beta-Lactamases/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA