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1.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445544

RESUMO

Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Citoplasma/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ácido Fólico/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Células Tumorais Cultivadas
2.
Food Funct ; 12(17): 7805-7815, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34231603

RESUMO

Liver fibrosis is a progression of chronic liver disease characterized by excess deposition of fibrillary collagen. The aim of this study was to investigate the protective effect of a triterpenoid-enriched extract (TEE) from bitter melon leaves against carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. Male ICR mice received TEE (100 or 150 mg kg-1) by daily oral gavage for one week before starting CCl4 administration and throughout the entire experimental period. After intraperitoneal injection of CCl4 for nine weeks, serum and liver tissues of the mice were collected for biochemical, histopathological and molecular analyses. Our results showed that TEE supplementation reduced CCl4-induced serum aspartate aminotransferase and alanine aminotransferase activities. Histopathological examinations revealed that CCl4 administration results in hepatic fibrosis, while TEE supplementation significantly suppressed hepatic necroinflammation and collagen deposition. In addition, TEE supplementation decreased α-smooth muscle actin (α-SMA)-positive staining and protein levels of α-SMA and transforming growth factor-ß1. TEE-supplemented mice had lower mRNA expression levels of interleukin-6, tumor necrosis factor-α, and toll-like receptor 4. Moreover, TEE (150 mg kg-1) supplementation significantly reduced intrahepatic inflammatory Ly6C+ monocyte infiltration. We demonstrated that TEE could ameliorate hepatic fibrosis by regulating inflammatory cytokine secretion and α-SMA expression in the liver to reduce collagen accumulation.

3.
Food Chem Toxicol ; 131: 110596, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226429

RESUMO

This study investigated the effects of chlorpyrifos (CPF) on immune-cell populations and intestinal inflammation using a mouse model of inflammatory bowel disease induced by dextran sulfate sodium (DSS). C57BL/6 mice were randomly assigned to five groups with one normal control (NC) and four DSS-treated groups. Mice in the NC group were given distilled water, whereas the DSS-treated groups received distilled water containing 3% DSS for 6 days to induce colitis. The NC and disease control (DC) groups were fed a control semipurified diet, while the remaining groups were exposed to CPF in the AIN-93 diet at doses of 1, 2.5, or 5 mg/kg/day throughout the study. Results showed that dietary exposure to CPF in colitic mice significantly increased circulating classical monocytes and upregulated gene expressions of chemokines in the colon compared to the NC group. Meanwhile, CPF exposure groups had lower plasma cholinesterase activities and higher percentages of circulating neutrophils than those of the DC group. A shorten length, tissue edema, and lipid peroxidation of the colon were also observed in all CPF-exposed mice. These findings suggest that dietary exposure to CPF affected immune-cell populations and inflammatory responses, which led to more severe tissue injury in mice with DSS-induced colitis.


Assuntos
Clorpirifos/toxicidade , Colite/imunologia , Leucócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana , Exposição Dietética , Leucócitos/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Molecules ; 23(8)2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30096960

RESUMO

Acne vulgaris (acne) is a common inflammatory skin disorder, and Propionibacterium acnes plays a major role in the development and progression of acne inflammation. Herbs possessing antimicrobial and anti-inflammatory activity have been applied as a medical option for centuries. In this study, we examined the suppressive effect of ethanolic oregano (Origanum vulgare) extract on live P. acnes-induced in vivo and in vitro inflammation. Following ethanol extraction of oregano leaves, four compounds with strong antioxidant activity, including rosmarinic acid, quercetin, apigenin, and carvacrol, were identified by high-performance liquid chromatography. Using the mouse ear edema model, we demonstrated that ethanol oregano extracts (EOE) significantly suppressed P. acnes-induced skin inflammation, as measured by ear thickness (32%) and biopsy weight (37%). In a separate study, using the co-culture of P. acnes and human THP-1 monocytes, EOE reduced the production of interleukin (IL)-8, IL-1ß and tumor necrosis factor (TNF)-α up to 40%, 37%, and 18%, respectively, as well as the expression of these three pro-inflammatory mediators at the transcriptional level. Furthermore, EOE inhibited the translocation of nuclear factor-kappa B (NF-κB) into the nucleus possibly by inactivating toll-like receptor-2 (TLR2). The suppressive effect of EOE on live P. acnes-induced inflammatory responses could be due, in part, to the anti-inflammatory and antioxidant properties, but not the anti-microbial effect of EOE.


Assuntos
Orelha/patologia , Edema/tratamento farmacológico , Etanol/química , Inflamação/tratamento farmacológico , Monócitos/microbiologia , Origanum/química , Extratos Vegetais/uso terapêutico , Propionibacterium acnes/efeitos dos fármacos , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Edema/microbiologia , Edema/patologia , Humanos , Inflamação/microbiologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos ICR , Monócitos/efeitos dos fármacos , Monócitos/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Fenóis/análise , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor 2 Toll-Like/metabolismo
5.
Int J Mol Sci ; 19(4)2018 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-29670037

RESUMO

Asthma is a chronic inflammatory disease affecting the airway, and it is characterized by a wheezing breathing sound, variable airflow obstruction and the presence of inflammatory cells in the submucosa of the bronchi. Viral infection, pollutants and sensitivity to aeroallergens damage the epithelium from childhood, which causes asthma. The pathogenesis of asthma includes pathways of innate stimulation by environmental microbes and irritant pathogens. Damaged epithelial cells produce thymic stromal lymphopoietin (TSLP) and stimulate myeloid dendritic cell maturation through the thymic stromal lymphopoietin receptor (TSLPR) heterocomplex. TSLP-activated myeloid dendritic cells promote naive CD4⁺ T cells to differentiate into T helper type 2 (Th2) phenotype CD4⁺ T cells. Re-exposure to allergens or environmental stimuli causes an adaptive immune response. TSLP-activated dendritic cells expressing the OX40 ligand (OX40L; CD252) trigger naive CD4⁺ T cells to differentiate into inflammatory Th2 effector cells secreting the cytokines interleukin-4, 5, 9, and 13 (IL-4, IL-5, IL-9 and IL-13), and the dendritic cells (DCs) promote the proliferation of allergen-specific Th2 memory cells. Allergen presentation by Th2 cells through its interaction with their receptors in the presence of major histocompatibility complex (MHC) class II on B cells and through costimulation involving CD40 and CD40L interactions results in immunoglobulin class switching from IgM to IgE. DCs and other blood cell subsets express the TSLPR heterocomplex. The regulatory mechanism of the TSLPR heterocomplex on these different cell subsets remains unclear. The TSLPR heterocomplex is composed of the IL-7Rα chain and TSLPR chain. Moreover, two isoforms of TSLP, short isoform TSLP (sfTSLP) and long isoform TSLP (lfTSLP), have roles in atopic and allergic development. Identifying and clarifying the regulation of TSLPR and IL-7Rα in pediatric asthma are still difficult, because the type of blood cell and the expression for each blood cell in different stages of atopic diseases are poorly understood. We believe that further integrated assessments of the regulation mechanism of the TSLP–TSLPR heterocomplex axis in vitro and in vivo can provide a faster and earlier diagnosis of pediatric asthma and promote the development of more effective preventive strategies at the onset of allergies.


Assuntos
Imunidade Adaptativa , Asma/imunologia , Citocinas/metabolismo , Imunidade Inata , Receptores de Citocinas/metabolismo , Criança , Humanos , Modelos Biológicos
6.
Life Sci ; 198: 25-31, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29549912

RESUMO

AIMS: This study uncovered that the genetically endowed intracellular glutathione contents (iGSH) regulated by the catalytic subunit of γ­glutamylcysteine synthetase heavy chain (γ­GCSh) as a prime target for overcoming both the inherited and stimuli-activated chemo- and radio-resistance of hepatocellular carcinoma (HCC) cells. MAIN METHODS: Reactive oxygen species (ROS) production and mitochondrial membrane potential (Δψm) were determined by the probe-based flow cytometry. The TUNEL assay was used as an index of radio-sensitivity and the MTT assay was used as an index of chemo-sensitivity against various anti-cancer agents. iGSH and γ­GCSh activity were measured by HPLC methods. γ­GCSh-overexpressing GCS30 cell line was established by tetracycline-controlled Tet-OFF gene expression system in SK-Hep-1 cells. KEY FINDINGS: The relative radio-sensitivities of a panel of five HCC cells were found to be correlated negatively with both the contents of iGSH and their corresponding γ­GCSh activities with an order of abundance being Hep G2 > Hep 3B > J5 > Mahlavu > SK-Hep-1, respectively. Similarly, the cytotoxicity response patterns of these HCC cells against arsenic trioxide (ATO), a ROS-producing anti-cancer drug, were exactly identical to the order of ranking instigated by the radiotherapy (RT) treatment. Next, γ­GCSh-overexpressing GCS30 cells were found to possess excellent ability to profoundly mitigate both the drop of Δψm and apoptotic TUNEL-positive cell population engendered by ATO, cisplatin, doxorubicin, and RT treatments. SIGNIFICANCE: Our data unequivocally demonstrate that γ­GCSh may represent a prime target for overcoming anti-cancer drugs and RT resistance for HCC cells.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Resistencia a Medicamentos Antineoplásicos , Glutamato-Cisteína Ligase/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Tolerância a Radiação , Antineoplásicos/farmacologia , Apoptose , Trióxido de Arsênio , Arsenicais/farmacologia , Catálise , Cromatografia Líquida de Alta Pressão , Células Hep G2 , Humanos , Potencial da Membrana Mitocondrial , Óxidos/farmacologia , Espécies Reativas de Oxigênio/metabolismo
7.
Eur J Pharm Biopharm ; 123: 9-19, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29154834

RESUMO

In the present study, we attempted to develop a lecithin-stabilized micellar drug delivery system (LsbMDDs) for loading docetaxel (DTX) to enhance its therapeutic efficacy and minimize systemic toxicity. A novel DTX-loaded LsbMDDs was optimally prepared by a thin-film hydration method and then hydrated with a lecithin nanosuspension while being subjected to ultrasonication. Physical characteristics of the optimized DTX-loaded LsbMDDs formulations were examined and found to have a mean size of <200 nm, an encapsulation efficiency of >90%, and drug loading of >6% with stability at room temperature and at 4 °C being longer than 2 and 7 days, respectively. The in vitro release of DTX from the DTX-loaded LsbMDDs was slower than that from the generic product of DTX (Tynen®). A cell viability assay demonstrated that the LsbMDDs showed better cytotoxicity than Tynen® against CT26 cancer cells. The in vivo antitumor efficacy of the DTX-loaded LsbMDDs was observed to be better than that of Tynen® in a CT26 tumor-bearing mice model. A high-dose regimen of the DTX-loaded LsbMDDs formulation showed greater inhibition of DU145 tumor growth than did Tynen®, but with less to similar systemic toxicity. An in vivo study also showed that a greater amount of drug was able to accumulate in the tumor site with the DTX-loaded LsbMDDs, and its maximal tolerable doses for single and repeated injections were 2-2.5-fold higher than those of Tynen®. In conclusion, the LsbMDDs could be a promising high drug-loaded nanocarrier for delivering hydrophobic chemotherapeutic agents that can enhance the efficacy of chemotherapy and reduce systemic toxicity.


Assuntos
Lecitinas/química , Taxoides/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Lecitinas/administração & dosagem , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Micelas , Nanopartículas/administração & dosagem , Nanopartículas/química , Tamanho da Partícula , Suspensões/química , Taxoides/administração & dosagem
8.
Tumour Biol ; 39(6): 1010428317702649, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28639913

RESUMO

We provide herein several lines of evidence to substantiate that folic acid (or folate) is a micronutrient capable of functioning as a novel redox regulator on hepatocellular carcinoma. First, we uncovered that folate deficiency could profoundly downregulate two prominent anti-apoptotic effectors including survivin and glucose-regulated protein-78. Silencing of either survivin or glucose-regulated protein-78 via small interfering RNA interfering technique established that both effectors could serve as reactive oxygen species sinker proteins. Second, folate deficiency-triggered oxidative-nitrosative stress could strongly induce endoplasmic reticulum stress that in turn could provoke cellular glutathione depletion through the modulation of the following two crucial events: (1) folate deficiency could strongly inhibit Bcl-2 expression leading to severe suppression of the mitochondrial glutathione pool and (2) folate deficiency could also profoundly inhibit two key enzymes that governing cellular glutathione redox regulation including γ-glutamylcysteinyl synthetase heavy chain, a catalytic enzyme for glutathione biosynthesis, and mitochondrial isocitrate dehydrogenase 2, an enzyme responsible for providing nicotinamide adenine dinucleotide phosphate necessary for regenerating oxidized glutathione disulfide back to glutathione via mitochondrial glutathione reductase. Collectively, we add to the literature new data to strengthen the notion that folate is an essential micronutrient that confers a novel role to combat reactive oxygen species insults and thus serves as a redox regulator via upregulating reactive oxygen species sinker proteins and averting mitochondrial glutathione depletion through proper maintenance of redox homeostasis via positively regulating glutathione biosynthesis, glutathione transporting system, and mitochondrial glutathione recycling process.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ácido Fólico/metabolismo , Proteínas de Choque Térmico/genética , Proteínas Inibidoras de Apoptose/genética , Neoplasias Hepáticas/tratamento farmacológico , Animais , Apoptose/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Estresse do Retículo Endoplasmático/genética , Ácido Fólico/genética , Regulação Neoplásica da Expressão Gênica , Glutationa/metabolismo , Proteínas de Choque Térmico/antagonistas & inibidores , Células Hep G2 , Homeostase , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Isocitrato Desidrogenase/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Oxirredução , Estresse Oxidativo/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Espécies Reativas de Oxigênio/metabolismo , Survivina
10.
JPEN J Parenter Enteral Nutr ; 41(5): 805-814, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-26231059

RESUMO

BACKGROUND: Sepsis is a common cause of death in critically ill patients. An overwhelming inflammatory response and imbalance of helper T (Th) cells and regulatory T (Treg) cells are thought to be involved in the progression of sepsis. ω-3 Polyunsaturated fatty acids (PUFAs) were found to have anti-inflammatory and immunomodulatory properties. This study investigated the effects of ω-3 PUFAs on the balance of Th subsets, Treg cells, and the inflammatory response in septic mice. METHODS: Mice were randomly assigned to soybean oil (SO) and fish oil (FO) groups. The 2 groups received an identical nutrient distribution except for the sources of the fat. The SO group was fed soybean oil, while part of the soybean oil was replaced by fish oil in the FO group. The FO group had an ω-6/ω-3 PUFA ratio of 2:1. After feeding the diets for 3 weeks, sepsis was induced by cecal ligation and puncture (CLP), and mice were sacrificed on days 0, 1, and 3. RESULTS: Compared with the SO group, the FO group had lower inflammatory mediator levels in the plasma and peritoneal lavage fluid after CLP. Also, the FO group had lower Th1, Th2, and Th17 percentages and a higher Th1/Th2 ratio in blood. In lung tissues, neutrophil infiltration was reduced, whereas peroxisome proliferator-activated receptor γ expression was upregulated. CONCLUSIONS: A fish oil diet with an ω-6/ω-3 PUFA ratio of 2:1 may elicit more balanced Th polarization, alleviate inflammatory responses, and attenuate lung injury in CLP-induced sepsis.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Homeostase/efeitos dos fármacos , Lesão Pulmonar/tratamento farmacológico , Sepse/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/química , Linfócitos T CD4-Positivos/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Ácidos Graxos Ômega-6/farmacologia , Óleos de Peixe/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/microbiologia
11.
Adv Healthc Mater ; 5(16): 2131-41, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27337051

RESUMO

A new therapeutic strategy of combining multistage short-term magnetic guidance with optimized ligand-mediated targeting in a newly developed nanodelivery system is investigated to promote accumulation and modulate intratumoral distribution behavior of the nanocarriers for enhanced tumor therapy. The multifunctional magnetic nanocarriers (MNCs) composed of single-component thiol-functionalized PVA/PMASH copolymer and superparamagnetic nanoparticles are developed for providing tunable dual-targeting ability and simultaneously modulating pH-responsive on/off drug release. Results show that plasma doxorubicin (Dox) concentration of the mice treated with Trastuzumab (Tra)-targeted Dox-MNCs can be rapidly decreased by applying dual-targeting treatment. More importantly, cooperative modulation of magnetic targeting and Tra density on the nanocarrier significantly optimize intratumoral distribution and enhance the utilization rate of nanomedicines within tumor to inhibit tumor growth. The mice treated with 2T-Dox-MNCs + multistage magnetic targeting (MT) (2 h d(-1) ) show 7.63-fold, 3.25-fold, and 2.7-fold reduction in HER2-positive tumor volume compared to Dox-MNCs, 2T-Dox-MNCs, and 2T-Dox-MNCs + single MT (12 h). The synergistic dual-targeting approach represents a major paradigm advance in tumor treatment and nanocarrier design in preclinical application.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina , Portadores de Fármacos , Campos Magnéticos , Nanopartículas , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
12.
PLoS One ; 11(2): e0149897, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26919045

RESUMO

The expression of cancer stemness is believed to reduce the efficacy of current therapies against hepatocellular carcinoma (HCC). Understanding of the stemness-regulating signaling pathways incurred by a specific etiology can facilitate the development of novel targets for individualized therapy against HCC. Niche environments, such as virus-induced inflammation, may play a crucial role. However, the mechanisms linking inflammation and stemness expression in HCC remain unclear. Here we demonstrated the distinct role of inflammatory mediators in expressions of stemness-related properties involving the pluripotent octamer-binding transcription factor 4 (OCT4) in cell migration and drug resistance of hepatitis B virus-related HCC (HBV-HCC). We observed positive immunorecognition for macrophage chemoattractant protein 1 (MCP-1)/CD68 and OCT4/NANOG in HBV-HCC tissues. The inflammation-conditioned medium (inflamed-CM) generated by lipopolysaccharide-stimulated U937 human leukemia cells significantly increased the mRNA and protein levels of OCT4/NANOG preferentially in HBV-active (HBV+HBsAg+) HCC cells. The inflamed-CM also increased the side population (SP) cell percentage, green fluorescent protein (GFP)-positive cell population, and luciferase activity of OCT4 promoter-GFP/luciferase in HBV-active HCC cells. Furthermore, the inflamed-CM upregulated the expressions of insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) and activated IGF-IR/Akt signaling in HBV-HCC. The IGF-IR phosphorylation inhibitor picropodophyllin (PPP) suppressed inflamed-CM-induced OCT4 and NANOG levels in HBV+HBsAg+ Hep3B cells. Forced expression of OCT4 significantly increased the secondary sphere formation and cell migration, and reduced susceptibility of HBV-HCC cells to cisplatin, bleomycin, and doxorubicin. Taking together, our results show that niche inflammatory mediators play critical roles in inducing the expression of stemness-related properties involving IGF-IR activation, and the upregulation of OCT4 contributes to cancer migration and drug resistance of HBV-HCC cells. Findings in this paper would provide potential targets for a therapeutic strategy targeting on inflammatory environment for HBV-HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Hepatite B Crônica/complicações , Neoplasias Hepáticas/patologia , Células-Tronco Neoplásicas/patologia , Fator 3 de Transcrição de Octâmero/biossíntese , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/biossíntese , Antígenos de Diferenciação Mielomonocítica/genética , Carcinoma Hepatocelular/virologia , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Células Hep G2 , Vírus da Hepatite B/patogenicidade , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Humanos , Inflamação/imunologia , Inflamação/patologia , Fator de Crescimento Insulin-Like I/biossíntese , Neoplasias Hepáticas/virologia , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/genética , Fosforilação/efeitos dos fármacos , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/biossíntese , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais , Esferoides Celulares , Células Tumorais Cultivadas
13.
JPEN J Parenter Enteral Nutr ; 40(3): 383-91, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25384382

RESUMO

BACKGROUND: This study investigated the effect of different ω-6/ω-3 polyunsaturated fatty acid (PUFA) ratios on dextran sulfate sodium (DSS)-induced changes to small intestinal intraepithelial lymphocyte (IEL) γδT-cell expression. METHODS: Mice were assigned to 3 control and 3 DSS-treated groups and were maintained on a low-fat semipurified diet. One of the control (S) groups and a DSS (DS) group were provided with soybean oil; the other 2 control (Hω-3 and Lω-3) groups and 2 other DSS (DHω-3 and DLω-3) groups were fed either a soybean and fish oil mixture with a ω-6/ω-3 ratio of 2:1 or 4:1. After feeding the respective diets for 2 weeks, the DSS groups were given distilled water containing 2% DSS, and the control groups were given distilled water for 5 days. All groups were further provided distilled water 5 days for recovery, and the small intestinal IEL γδT-cell subset was isolated for analysis. RESULTS: DSS treatment resulted in a lower small intestinal IEL γδT-cell percentage and higher messenger RNA (mRNA) expressions of Reg IIIγ, keratinocyte growth factor (KGF), and complement 5a receptor (C5aR) by IEL γδT cells. Fish oil administration enhanced the proportion of small intestinal IEL γδT cells. Compared with the DLω-3 group, the DHω-3 group had lower Reg IIIγ, KGF, and C5aR mRNA expressions and higher expression of peroxisome proliferator-activated receptor (PPAR)-γ gene by small intestinal IEL γδT cells. CONCLUSIONS: Fish oil diets with a ω-6/ω-3 PUFA ratio of 2:1 were more effective than those with a ratio of 4:1 in improving DSS-induced small intestinal injury, and activation of PPAR-γ in IEL γδT cells may be associated with resolution of small intestinal inflammation.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Óleos de Peixe/farmacologia , Intestino Delgado/efeitos dos fármacos , Óleo de Soja/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Peso Corporal , Quimiocina CCL2/metabolismo , Sulfato de Dextrana/toxicidade , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Ácidos Graxos Ômega-3/análise , Ácidos Graxos Ômega-6/análise , Fator 7 de Crescimento de Fibroblastos/genética , Fator 7 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Intestino Delgado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/genética , PPAR gama/metabolismo , Proteínas Associadas a Pancreatite , Lavagem Peritoneal , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
14.
Oncotarget ; 6(28): 26104-18, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26327128

RESUMO

Patients with hepatocellular carcinoma (HCC) are prone to folate deficiency (FD). Here we showed that, in cell line-specific manner, FD caused resistance to FD-induced oxidative stress and multi-drug resistance (MDR). This resistance was due to upregulation of glucose-regulated protein 78 (GRP78) and Survivin. Using siRNA and Epigallocatechin gallate (EGCG), we found that GRP78 and Survivin cooperatively conferred MDR by decreasing FD-induced ROS generation. Our data showed that FD increases GRP78 and Survivin, which serve as ROS inhibitors, causing MDR in HCC. We suggest that folate supplementation may enhance the efficacy of chemotherapy.


Assuntos
Ácido Fólico/farmacologia , Proteínas de Choque Térmico/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Catequina/análogos & derivados , Catequina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Meios de Cultura/metabolismo , Meios de Cultura/farmacologia , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Ácido Fólico/metabolismo , Proteínas de Choque Térmico/genética , Células Hep G2 , Humanos , Proteínas Inibidoras de Apoptose/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Oxirredução , Interferência de RNA , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Survivina
15.
PLoS One ; 10(9): e0136340, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26355599

RESUMO

Here, we present evidence of a novel microtubule-disrupting agent, N-deacetyl-N-(chromone-2-carbonyl)-thiocolchicine (TCD), exhibiting potent antitumor activity (with IC50 values in the nanomolar range) against hepatocellular carcinoma cell lines. Cell cycle analysis revealed that TCD induced G2/M cell-cycle arrest in a dose- and time-dependent manner in both Hep-J5 and Mahlavu HCC cell lines. TCD also induced a decrease in mitochondrial membrane potential (ΔΨm) and caused DNA damage. Mechanistically, TCD activated protein kinase RNA-like endoplasmic reticular kinase and several transcription factors, including activating transcription factor (ATF) 6, ATF4, ATF3, and the CCAAT-enhancer binding protein homologous protein. These data clearly demonstrate that the antitumor activity of TCD is mechanistically linked to its capacity to trigger both intrinsic and extrinsic apoptotic cell death via endoplasmic reticular stress pathway. The potent antitumor activity of TCD was similarly demonstrated in a hepatocellular carcinoma xenograft model, where 5 and 10 mg/kg doses of TCD significantly arrested Hep-J5 and Mahlavu tumor growth. Our finding suggests that TCD is a promising therapeutic agent against hepatocellular carcinoma; further translational assessment of its clinical usage is warranted.


Assuntos
Carcinoma Hepatocelular/patologia , Colchicina/análogos & derivados , Estresse do Retículo Endoplasmático , Neoplasias Hepáticas/patologia , Microtúbulos/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/enzimologia , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Colchicina/farmacologia , Colchicina/uso terapêutico , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Concentração Inibidora 50 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/enzimologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microtúbulos/efeitos dos fármacos , Chaperonas Moleculares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
16.
Int J Mol Sci ; 16(8): 19387-400, 2015 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-26287183

RESUMO

15,16-Dihydrotanshinone I (DHTS) is extracted from Salvia miltiorrhiza Bunge which is a functional food in Asia. In this study, we investigated the apoptotic effect of DHTS on the human acute myeloid leukemia (AML) type III HL-60 cell line. We found that treatment with 1.5 µg/mL DHTS increased proapoptotic Bax and Bad protein expressions and activated caspases-3, -8, and -9, thus leading to poly ADP ribose polymerase (PARP) cleavage and resulting in cell apoptosis. DHTS induced sustained c-Jun N-terminal kinase (JNK) phosphorylation and Fas ligand (FasL) expression. The anti-Fas blocking antibody reversed the DHTS-induced cell death, and the JNK-specific inhibitor, SP600125, inhibited DHTS-induced caspase-3, -8, -9, and PARP cleavage. In a xenograft nude mice model, 25 mg/kg DHTS showed a great effect in attenuating HL-60 tumor growth. Taken together, these results suggest that DHTS can induce HL-60 cell apoptosis in vitro and inhibit HL-60 cell growth in vivo; the underlying mechanisms might be mediated through activation of the JNK and FasL signal pathways.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Leucemia/tratamento farmacológico , Fenantrenos/uso terapêutico , Salvia miltiorrhiza/química , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Alimento Funcional/análise , Células HL-60 , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Leucemia/metabolismo , Leucemia/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Fenantrenos/química , Fenantrenos/isolamento & purificação
17.
J Neurooncol ; 124(3): 403-12, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26239968

RESUMO

Colchicine, an anti-microtubule and antimitotic drug, is a common therapeutically agent for gout, which is thought to have potential anti-tumor effects. Owing to concerns of colchicines poisoning, the development of derivatives with low dose efficacy and less side effects is of obvious interest. In this study, we characterized the inhibitory effects of a colchicine derivative named AD1 on the cell proliferation of human malignant glioblastoma (MG) cell lines, U87MG and U373MG. We found that 50 % of U87MG and U373MG cells were reduced in the cultures after exposure to AD1 for 24 h at 10 and 50 nM, respectively. Moreover, α-tubulin immunostaining indicated that AD1 induced the disruption of the microtubule polymerization in glioma cells with apoptotic features including membrane budding/blebbing or fragmented nuclei. Increased levels of reactive oxygen species (ROS) were also detected in AD1-treated U87MG and U373MG cells compared to that observed in the control culture. Moreover, examination of microtubule-associated protein 1A/1B-light chain 3 (LC3I)/LC3II conversion and acridine orange staining for autophagic vesicles, combined with flow cytometry, showed that treatment with AD1 induced the autophagic pathway in U87MG and U373MG cells. Furthermore, we found that the intermittent intravenous administration of AD1 suppressed glioma growth in rat brain receiving intracerebral injection with rat C6 glioma cells. Taken together, our findings reveal that treatment with AD1 at nanomolar scales can reduce glioma cell viability effectively, with the occurrence of a rise in ROS and cellular autophagy. In conjunction with the observations from in vivo study, the colchicine derivative AD1 has chemotherapeutic potential to suppress glioma progression.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Colchicina/uso terapêutico , Glioblastoma/tratamento farmacológico , Animais , Autofagia/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Colchicina/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Glioblastoma/patologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Clin Cancer Res ; 21(1): 201-10, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25564572

RESUMO

PURPOSE: To unravel the role of interleukin (IL)-6 and insulin-like growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGFIR expression levels in tissues (n = 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan-Meier survival analysis. RESULTS: A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo. CONCLUSIONS: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC.


Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Homeodomínio/biossíntese , Interleucina-6/sangue , Neoplasias Hepáticas/genética , Fator 3 de Transcrição de Octâmero/biossíntese , Receptores de Somatomedina/biossíntese , Animais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Vírus da Hepatite B/patogenicidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/virologia , Camundongos , Proteína Homeobox Nanog , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Nanomedicine (Lond) ; 10(8): 1263-74, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25479463

RESUMO

AIM: A thermosensitive injectable hydrogel composed of nanocomplexes of doxorubicin and hyaluronic acid (HA) for the local treatment of cancer diseases was developed and characterized. MATERIALS & METHODS: It was found that the addition of a divalent metal ion of Mg (MgCl2) was required to properly form HA-doxorubicin nanocomplexes, which were mixed with Pluronic® F127 (BASF, Germany) to form thermosensitive injectable hydrogels. RESULTS: The DH700KMF-15 hydrogel resulted in efficient growth inhibition of C26 colon cancer cells and it selectively targeted the lymphatic system by the specific affinity of HA to the lymphatic system in vivo. CONCLUSION: The optimal formulations of DH700KMF-15 can increase the therapeutic efficacy of the local treatment of cancer with the potential for lymphotropic targeting to inhibit metastasis.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Preparações de Ação Retardada/química , Doxorrubicina/administração & dosagem , Ácido Hialurônico/química , Hidrogéis/química , Poloxâmero/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias do Colo/patologia , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Humanos , Injeções , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transição de Fase , Temperatura
20.
Tumour Biol ; 35(6): 6047-54, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24633886

RESUMO

Thrombomodulin (TM) is highly expressed in endothelial cells and plays the key role in maintaining physical homeostasis. In addition, many pieces of evidence also show that TM contains the diagnostic value for malignant diseases. TM has been found to correlate with metastatic status in multiple cancers, but its role in prostate cancer progression remains unclear. TM expression was determined in prostate cancer cells (DU-145 and PC-3 cells) using real-time PCR and Western blotting. TM expression was manipulated in prostate cancer cells using TM-specific shRNA and an overexpression system. The proliferation, adhesion, and migratory ability of prostate cancer cells expressing various TM levels were determined using the x'Celligence biosensor system and a transwell migration assay. Higher levels of TM transcription and translation were found in DU-145 cells and were negatively correlated with the low migratory ability of DU-145 cells. After silencing TM expression in DU-145 cells, cell growth decreased, but cell adhesion and migration dramatically increased. TM overexpression in PC-3 cells reduced their metastatic ability. We investigated the possible mechanisms of this phenomenon and determined that the enhanced cell migration was mediated through the expression of E-cadherin and vimentin. TM may be a modulator of hormone-independent prostate cancer (HIPC) metastasis. The downregulation of TM expression enhanced the migratory ability of these cells via an increase in vimentin expression and a decrease in E-cadherin expression.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias da Próstata/patologia , Trombomodulina/fisiologia , Biomarcadores , Caderinas/análise , Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Masculino , Vimentina/análise
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