RESUMO
Chronic obstructive pulmonary disease (COPD) often tends to respond poorly to glucocorticoid (GC) therapy. Reduced Histone deacetylase-2 (HDAC-2) activity is an important mechanism behind this GC insensitivity. In this study, we investigated the effects of three phosphodiesterase inhibitors (PDEIs), with an anti-inflammatory propensity, on cigarette smoke (CS)-induced pulmonary inflammation and HDAC-2 activity. Male C57BL/6 mice were exposed to cigarette smoke (CS) over the course of 30 weeks. Administration of the PDEIs commenced from the 29th week and followed a schedule of once daily treatments, 5 days a week, for 2 weeks. Roflumilast (ROF) was administered intragastrically (5 mg·kg-1 ), while pentoxifylline (PTX) (10 mg·kg-1 ) and theophylline (THEO) (10 mg·kg-1 ) were administered intraperitoneally, either alone or in combination with a GC (triamcinolone acetonide or TRI, 5 mg·kg-1 , i.m., single injection). Lung morphometry, as well as the activity of HDAC-2, pro-inflammatory cytokines and reactive oxygen species (ROS) were assessed at the end of the 30-week course. CS exposure was associated with a reduction in HDAC-2 activity and the up-regulation of ROS expression. PTX, ROF, and THEO administration led to the partial restoration of HDAC-2 activity, which was favorably associated with the reduction of ROS expression. However, combining TRI to any of these PDEIs did not synergistically augment HDAC-2 activity. Inactivation of HDAC-2 due to long-term CS exposure is closely related to exaggerated oxidative stress, and this reduced HDAC-2 activity could partially be restored through the use of PDEIs. This finding provides a potential novel approach for further clinical research.
Assuntos
Aminopiridinas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzamidas/uso terapêutico , Pentoxifilina/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Teofilina/uso terapêutico , Aminopiridinas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Modelos Animais de Doenças , Histona Desacetilase 2/metabolismo , Interleucina-8/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Pentoxifilina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Espécies Reativas de Oxigênio/metabolismo , Fumaça/efeitos adversos , Fumar/efeitos adversos , Teofilina/farmacologia , Nicotiana , Fator de Necrose Tumoral alfa/imunologiaRESUMO
In attempts to delay tumor progression after surgery or minimally invasive local treatments, multidisciplinary strategies have been broadly studied in patients with hepatocellular carcinoma (HCC). The objective of this present study was to evaluate the efficacy of autologous transplantations of cytokine-induced killer (CIK) cells as an adjuvant therapy for patients with HCC. A total of 264 patients with HCC were enrolled in this retrospective study. Of these patients, 165 received either CIK cell therapy alone or as adjuvant therapy to surgery, transcatheter arterial chemoembolization (TACE), or TACE-based comprehensive treatments (CT). The remaining 99 patients received only surgery or TACE. Kaplan-Meier analysis and the Chi-squared test were used to analyze the overall survival (OS), progression-free survival (PFS), and clinical characteristics of the patients in the different treatment subgroups. Kaplan-Meier analysis suggested that patients in the Surgery+CIK group had a significantly improved OS compared with those in the other three groups (P < 0.001). Furthermore, patients who developed a fever after the CIK cell treatments manifested a likely better OS (P = 0.028). Subgroup analysis indicated that patients in the Surgery+CIK group likely had an improved PFS but a similar OS compared with the patients in the Surgery-alone group (P = 0.055 for PFS, and P = 0.746 for OS). Further subgroup analysis showed that the OS in both the TACE+CIK and CT+CIK groups was prolonged significantly compared with that in the TACE-alone group (P = 0.015 and P = 0.018, respectively). However, similar OS was observed between the TACE+CIK and CT+CIK groups (P = 0.686). Autologous transplantation of CIK cells as an adjuvant therapy was associated with better survival for patients with HCC, especially for those who had also undergone TACE. A fever reaction might be a potential event for assessing the curative effect of the CIK treatment.
RESUMO
Colon cancer is one of the most common malignant tumors worldwide. Understanding the underlying molecular mechanisms is crucial for the development of therapeutic strategies for the treatment of patients with colon cancer. In the present study, a novel tumor suppressive microRNA, miR192, was demonstrated to be markedly downregulated in colon cancer cells compared with normal colon cells. By overexpressing miR192 in colon cancer HCT116 cells, the results of the present study revealed that miR192 inhibits cell proliferation, migration and invasion. Bioinformatics were used to determine the target gene of miR192 and Rasrelated protein Rab2A (RAB2A) was identified as a downstream target of miR192. Following the determination of the role of the miR192RAB2A pathway in colon cancer, small molecules that may regulate miR192 were screened and the results demonstrated that simvastatin is an activator of miR192. Furthermore, simvastatin upregulated miR192 and inhibited the expression of downstream targets of miR192, which subsequently led to suppressed proliferation, migration and invasion of colon cancer cells. In conclusion, the present study identified a novel colon cancer cell suppressor, as well as a smallmolecule activator of the tumor suppressor miR192, which may represent a therapeutic strategy for the treatment of patients with colon cancer.
Assuntos
Carcinogênese/genética , Neoplasias do Colo/genética , MicroRNAs/genética , Sinvastatina/farmacologia , Proteínas rab de Ligação ao GTP/genética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Supressores de Tumor , Células HCT116 , Humanos , Transdução de Sinais/efeitos dos fármacosRESUMO
The present article reports a novel biosensor for organophosphorus pesticides based on fluorescence resonance energy transfer (FRET) between nitrogen-doped carbon dots (NC-dots) and gold nanoparticles (AuNPs). The effective NC-dots/AuNPs assembly through the Au-N interaction results in good fluorescence quenching. Active acetylcholinesterase (AChE) catalyzes the hydrolysis of acetylthiocholine into -SH containing thiocholine to replace the NC-dots and trigger the aggregation of AuNPs. In the presence of paraoxon, the activity of AChE is inhibited, and thus preventing the generation of thiocholine, causing fewer NC-dots to be replaced. As a consequence, the fluorescence intensity gradually decreases with increasing amount of paraoxon. This biosensor does not require any complex synthesis or modification, and the results show a wide detection range of from 10(-4) to 10(-9) g/L with a detection limit of 1.0 × 10(-9) g/L (3.6 × 10(-12) mol/L). Two linear response regions have been reported with a turning point at about 10(-6) g/L and three different factors that would influence the response behavior. These phenomena discussed in detail so as to explain the special response mechanism.