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1.
Eur J Med Chem ; 198: 112366, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32371335

RESUMO

NF-κB is a key signaling pathway molecule linking hepatoma and chronic inflammation. Inhibition of NF-κB activation can alleviate inflammation, and promote hepatoma cell apoptosis. In this study, a series of fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines (PPMs, 31-57) were synthesized from 3,5-bis(arylidene)-4-piperidones (BAPs, 4-30) based on scaffold hopping. We successfully discovered the most potent 43 substituted by electron-withdrawing substitutes (3-F and 4-CF3) exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 43 induced dose-dependent cell apoptosis at cell and protein level, while inhibited NF-κB activation by suppressing LPS-induced phosphorylation levels of p65, IκBα and Akt, and by indirectly suppressing MAPK signaling, and by inhibiting the nuclear translocation of NF-κB induced by TNF-α or LPS. Docking analysis verified simulated 43 could reasonably bind to the active site of Bcl-2, p65 and p38 proteins. This compound, as a novel NF-κB inhibitor, also demonstrated both anti-inflammatory and anti-hepatoma activities, warranting its further development as a potential multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.

2.
BMC Pulm Med ; 20(1): 45, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070324

RESUMO

BACKGROUND: Bronchiectasis is a chronic infectious respiratory disease with diverse causes and ethnic or geographic differences. However, few large-scale studies of its etiology have been conducted in Asia. This study aimed to determine the etiology and clinical features of bronchiectasis in Taiwan. METHODS: This longitudinal cohort study investigated the etiology and clinical features of newly diagnosed non-cystic fibrosis bronchiectasis patients from January 2002 to December 2016. The clinical, functional and microbiological data of patients were retrieved from the Chang Gung Research Database, which includes seven medical facilities throughout Taiwan. The index date was the date of the first bronchiectasis diagnosis. Known diseases that were diagnosed before the index date were regarded as etiologies of bronchiectasis. RESULTS: The cohort comprised 15,729 adult patients with bronchiectasis. Idiopathic (32%) was the most common cause, followed by post-pneumonia (24%). Other causes included post-tuberculosis (12%), chronic obstructive pulmonary disease (14%), asthma (10%), gastroesophageal reflux disease (2%) and rheumatic diseases (2%). At diagnosis, 8487 patients had sputum culture. Pseudomonas aeruginosa (5.3%) was the most common bacteria, followed by non-tuberculosis mycobacteria (3.6%), Haemophilus influenzae (3.4%) and Klebsiella pneumoniae (3.1%), but 6155 (72.1%) had negative sputum cultures. Patients with post-tuberculosis had a higher sputum isolation rate of non-tuberculosis mycobacteria than P. aeruginosa. Patients with post-tuberculosis and post-pneumonia bronchiectasis had a higher frequency of chronic lung infection than other groups (p < 0.05). Clinical characteristics, such as gender, lung function, comorbidities and microbiology, were significantly different between idiopathic and known etiologies. CONCLUSIONS: Idiopathic, post-infection and tuberculosis constitute major bronchiectasis etiologies in Taiwan. Clinical characteristics and sputum microbiology were distinct among separate etiology phenotypes.

3.
Mol Oncol ; 14(2): 373-386, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31670863

RESUMO

Hepatocellular carcinoma (HCC), with its ineffective therapeutic options and poor prognosis, represents a global threat. In the present study, we show that RAD52 motif 1 (RDM1), a key regulator of DNA double-strand break repair and recombination, is downregulated in HCC tissues and suppresses tumor growth. In clinical HCC samples, low expression of RDM1 correlates with larger tumor size, poor tumor differentiation, and unfavorable survival. In vitro and in vivo data demonstrate that knockdown of RDM1 increases HCC cell proliferation, colony formation, and cell population at G2/M phase, whereas RDM1 overexpression results in the opposite phenotypes. Mechanistically, RDM1 binds to the tumor suppressor p53 and enhances its protein stability. In the presence of p53, RDM1 suppresses the phosphorylation of Raf and ERK. Overexpression of p53 or treatment with ERK inhibitor significantly abolishes cell proliferation induced by the depletion of RDM1. In addition, overexpression of methyltransferase-like 3 markedly induces N6-methyladenosine modification of RDM1 mRNA and represses its expression. Taken together, our study indicates that RDM1 functions as a tumor suppressor and may be a potential prognostic and therapeutic factor for HCC.

4.
Bioorg Chem ; 94: 103350, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31640933

RESUMO

One new polycyclic furanobutenolide-derived norcembranoid, xiguscabrolide H (1), together with eleven known related norditerpenoids 2-12 were isolated from South China Sea soft corals Sinularia scabra and S. polydactyla, respectively. Among them, compounds 1, 6, 8, and 12 were discovered from the former species, while compounds 2-5, 7, and 9-11 were obtained from the latter species. The structure of new compound 1 was elucidated by extensive spectroscopic analysis and by the comparison with the reported data. With the assistance of time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) calculations, its absolute configuration was determined. Moreover, the absolute stereostructures of the known compounds 3, 4, and 9-12, of which only relative configurations were assigned, were established for the first time by X-Ray diffraction analysis and TDDFT-ECD calculations, respectively. In bioassay, several isolates exhibited potent inhibitory effects on the ConA-induced T lymphocytes and/or LPS-induced B lymphocytes proliferation.

5.
Biomed Res Int ; 2019: 6171065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886233

RESUMO

Tazarotene-induced gene 1 (TIG1) encodes a protein that is a retinoid-regulated tumor suppressor. TIG1 is expressed in most normal tissues, and downregulation of TIG1 expression in multiple cancers is caused by promoter hypermethylation. Kazal-type serine protease inhibitor-2 (SPINK2) is a serine protease inhibitor, and the SPINK protein family has been shown to inhibit the expression of urokinase-type plasminogen activator (uPA). In addition, increased levels of uPA and the uPA receptor were observed in testicular cancer tissues. This study demonstrated that TIG1 interacts with SPINK2 in NT2/D1 testicular carcinoma cells. TIG1 and SPINK2 were highly expressed in normal testis tissues, while low expression levels of TIG1 and SPINK2 were found in testicular cancer tissues. TIG1 inhibited cell invasion, migration, and epithelial-mesenchymal transition (EMT) of NT2/D1 cells. SPINK2 enhanced TIG1-regulated uPA activity and EMT suppression, while silencing SPINK2 alleviated TIG1-mediated EMT regulation, cell migration, and invasion. Therefore, the results suggest that the interaction between TIG1 and SPINK2 plays an important role in the inhibition of testicular cancer cell EMT, and suppression is mediated through downregulation of the uPA/uPAR signaling pathway.


Assuntos
Glicoproteínas , Proteínas de Membrana , Invasividade Neoplásica/genética , Inibidores de Serinopeptidase do Tipo Kazal , Neoplasias Testiculares/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Inativação Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Inibidores de Serinopeptidase do Tipo Kazal/genética , Inibidores de Serinopeptidase do Tipo Kazal/metabolismo , Neoplasias Testiculares/genética
6.
Sci Rep ; 9(1): 19839, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882693

RESUMO

Streptococcus pneumonia, one of the major colonizers in nasopharyngeal adenoids, has been the predominant pathogen causing acute otitis media (AOM) in children. Recent evidence suggests an association between IL-17A-mediated immune response and the clearance of pneumococcal colonization in nasopharyngeal adenoids. Here, we evaluated the expressions of IL-17A and associated genes in hypertrophic adenoid tissues of children with sleep-disordered breathing (SDB) and otitis media with effusion (OME) and their association with pneumococcal carriage. Sixty-six pediatric patients with adenoid hypertrophy were enrolled. During adenoidectomy, nasopharyngeal swab and adenoid tissues were used to determine pneumococcal carriage and IL-17A expression. Our results revealed significantly higher levels of IL-17A and IL-17A:IL-10 mRNA in the SDB patients positive for nasopharyngeal pneumococcal carriage than those negative. However, these differences were not significant in the OME group. These results suggested, in OME patients, prolonged or chronic pneumococcal carriage may occur because of insufficient IL-17A-mediated mucosal clearance, and could further lead to AOM and OME development.

7.
Toxicol Appl Pharmacol ; 384: 114787, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669718

RESUMO

Zinc oxide nanoparticles (ZnONPs) are widely used in the manufacturing of many commercial products. Workers exposed to ZnO particles may develop metal fume fever. Our previous study suggested that the oropharyngeal aspiration of ZnONPs could cause eosinophilic airway inflammation and increase T helper 2 (Th2) cytokine expression in the absence of allergens in mice. ZnO has been used topically as a sunscreen and a therapeutic agent for dermatological conditions. To understand whether inhalation and topically applied ZnONPs might cause or exert an adjuvant effect on the development of allergic airway inflammation in mice, C57BL/6 J mice were exposed to filtered air or 2.5 mg/m3 ZnONPs via whole-body inhalation for 5 h a day over 5 days, and BALB/c mice were topically exposed to ZnONPs using modified mouse models of atopic dermatitis (AD) and asthma. Ovalbumin (OVA) solution was used as an allergen in the topical exposure experiments. A significantly increased eosinophil count and mixed Th1/Th2 cytokine expression were detected in the bronchoalveolar lavage fluid (BALF) after ZnONP inhalation. However, only mild eosinophilia and low Th2 cytokine expression were detected in the BALF after oropharyngeal OVA aspiration in the high-dose ZnONP topical treatment group. These results suggest that ZnONP inhalation might play a role in the development of allergic airway inflammation in mice. However, topically applied ZnONPs only play a limited role in the development of allergic airway inflammation in mice.

8.
Sci Rep ; 9(1): 15357, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653934

RESUMO

A potential mechanism underlying cigarette smoke-induced airway disease is insufficient tissue repair via altered production of matrix metalloproteinases (MMPs). Osteitis is a signature feature of recalcitrant chronic rhinosinusitis (CRS) and often results in revision surgery. The present study aimed to investigate MMP expression in the nasal tissues of asthmatic patients with CRS and any association with cigarette smoking and osteitis. Thirteen smokers with CRS and asthma, 16 non-smokers with CRS and asthma, and seven non-smoker asthmatic patients without CRS were prospectively recruited. The expression of MMPs and associated immunological factors in surgically-obtained nasal tissues was evaluated via real-time PCR and western blotting. Maximal bone thickness of the anterior ethmoid (AE) partition was measured in axial sinus computed tomography (CT) sections. MMP-1 and MMP-9 expression was increased in the nasal tissues of smokers with asthma and CRS via real-time PCR and western blot. Maximal AE partition bone thickness was greater in smokers with CRS and asthma than in non-smokers with CRS and asthma. MMP-1 and MMP-9 levels were correlated with maximal AE bone thickness. Cigarette smoking was associated with the up-regulation of MMP-1 and MMP-9 in the nasal tissues of patients with airway inflammatory diseases, and with AE osteitis, and with therapeutic resistence.

9.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(4): 466-470, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31642220

RESUMO

OBJECTIVE: To detect cardiac amyloidosis (CA) using cardiac magnetic resonance feature tracking(CMR-FT). METHODS: Forty-three CA patients and 24 healthy volunteers underwent steady-state free precession cine sequence on 3.0T MRI after injection of Magnevist. Software cvi 42 was used for analyzing the left ventricular function including left ventricular mass (diastole) (LVMD), left ventricular mass (systole) (LVMS), left ventricle end-diastolic volume (LVEDV), left ventricle end-systolic volume (LVESV), left ventricle stroke volume (LVSV), and left ventricular ejection fraction (LVEF), as well as myocardial strains including 3D global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS), and 2D endocardial and epicardial longitudinal strain, circumferential strain, and radial strain (ENDO-LS, EPI-LS, ENDO-CS, EPI-CS, ENDO-RS, and EPI-RS). The global and layer-specific strains were compared between the CA patients with LVEF >50%, the CA patients with LVEF ≤50%, and the healthy controls. RESULTS: For the left ventricular function, the CA patients had greater myocardial mass than the healthy controls (P < 0.05); the CA patients with LVEF ≤50% had greater LVESV and lower LVSV than those with LVEF >50% (P < 0.05). For the global strains, significant differences also appeared in GLS and GCS among the three groups (all P < 0.05). The CA patients had lower GRS than the healthy controls (P < 0.05), while no significant difference was found in GRS between the CA patients with LVEF >50% and those with LVEF ≤50% (P>0.05). For the layer-specific strains, significant differences in ENDO-LS, EPI-LS, ENDO-CS, EPI-CS, ENDO-RS, and EPI-RS were found among the three groups (all P < 0.05). There were significant correlations between GLS and LVEF (r=-0.404, P=0.016), and between GCS and LVEF (r=-0.602, P < 0.001) in the CA patients. CONCLUSION: CMR-FT can assess not only global strains but also layer-specific strains for the myocardial function of CA patients.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Imagem por Ressonância Magnética , Função Ventricular Esquerda , Estudos de Casos e Controles , Humanos , Reprodutibilidade dos Testes , Volume Sistólico , Sístole
10.
Nutrients ; 11(10)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547048

RESUMO

BACKGROUND: Recently, we demonstrated that Astragalus polysaccharide (PG2), the active ingredient in dried roots of astragalus membranaceus, ameliorates cancer symptom clusters and improves quality of life (QoL) in patients with metastatic disease by modulating inflammatory cascade against the background roles of inflammatory cells, including macrophages, dendritic cells (DCs), and cytotoxic T lymphocytes (CTLs) in tumor initiation, metastasis, and progression. Nevertheless, the role of PG2 in the modulation of anticancer immunogenicity and therapeutic response remains relatively underexplored and unclear. PURPOSE: The present study investigates how and to what extent PG2 modulates cellular and biochemical components of the inflammatory cascade and enhances anticancer immunity, as well as the therapeutic implication of these bio-events in patients with lung cancer. METHODS AND RESULTS: Herein, we demonstrated that PG2 significantly increased the M1/M2 macrophage polarization ratio in non-small cell carcinoma (NSCLC) H441 and H1299 cells. This PG2-induced preferential pharmacologic up-regulation of tumoral M1 population in vitro positively correlated with the downregulation of tumor-promoting IL-6 and IL-10 expression in NSCLC cell-conditioned medium, with concomitant marked inhibition of cell proliferation, clonogenicity, and tumorsphere formation. Our ex vivo results, using clinical sample from our NSCLC cohort, demonstrated that PG2 also promoted the functional maturation of DCs with consequent enhancement of T cell-mediated anticancer immune responses. Consistent with the in vitro and ex vivo results, our in vivo studies showed that treatment with PG2 elicited significant time-dependent depletion of the tumor-associated M2 population, synergistically enhanced the anti-M2-based anticancer effect of cisplatin, and inhibited xenograft tumor growth in the NSCLC mice models. Moreover, in the presence of PG2, cisplatin-associated dyscrasia and weight-loss was markedly suppressed. CONCLUSION: These results do indicate a therapeutically-relevant role for PG2 in modulating the M1/M2 macrophage pool, facilitating DC maturation and synergistically enhancing the anticancer effect of conventional chemotherapeutic agent, cisplatin, thus laying the foundation for further exploration of the curative relevance of PG2 as surrogate immunotherapy and/or clinical feasibility of its use for maintenance therapy in patients with lung cancer.


Assuntos
Antineoplásicos/farmacologia , Astragalus propinquus/química , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Células Dendríticas/efeitos dos fármacos , Galectina 3/efeitos dos fármacos , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Neoplasias Pulmonares/imunologia , Antígeno de Macrófago 1/efeitos dos fármacos , Camundongos , Qualidade de Vida , Linfócitos T/efeitos dos fármacos
11.
J Clin Med ; 8(9)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547356

RESUMO

Chronic asthma is associated with progressive airway remodeling, which may contribute to declining lung function. An increase in matrix metalloproteinases-9 (MMP-9)/tissue inhibitor metalloproteinase-1 (TIMP-1) may indicate airway inflammation and bronchial injury. Bronchial biopsy specimens and alveolar macrophages (AMs) were obtained from patients with asthma under regular treatment with inhaled corticosteroids or combination therapy and normal subjects (n = 10). Asthmatics included those with a slow forced expiratory volume in one second (FEV1) decline (<30 mL/year, n = 13) and those with a fast FEV1 decline (≥30 mL/year, n = 8) in 5-year follow-up. Immunostaining expression of MMP-9 and TIMP-1 was detected in airway tissues. MMP-9 and TIMP-1 was measured from AMs cultured for 24 h. After the 5-year treatment, the methacholine airway hyperresponsiveness of the slow FEV1 decline group was decreased, but that of the fast FEV1 decline group was increased (PC20, provocative concentration causing a 20% decrease in FEV1, 3.12 ± 1.10 to 1.14 ± 0.34 mg/dL, p < 0.05). AMs of asthma with a fast FEV1 decline released a higher level of MMP-9 (8.52 ± 3.53 pg/mL, p < 0.05) than those of a slow FEV1 decline (0.99 ± 0.20 pg/mL). The MMP-9/TIMP ratio in the fast FEV1 decline group (0.089 ± 0.032) was higher than that of the slow FEV1 decline group (0.007 ± 0.001, p < 0.01). The annual FEV1 decline in 5 years was proportional to the level of MMP-9 (r = 57, p < 0.01) and MMP-9/TIMP-1 ratio (r = 0.58, p < 0.01). The airways of asthma with greater yearly decline in FEV1 showed an increased thickness of submucosa and strong expression of MMP-9. An increase in MMP-9 and MMP-9/TIMP-1 in airways or AMs could be indicators of chronic airway inflammation and contribute to a greater decline in lung function of patients with chronic asthma.

12.
Cancers (Basel) ; 11(8)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349728

RESUMO

Background: Improving patients' quality of life (QoL) is a principal objective of all treatment in any clinical setting, including oncology practices. Cancer-associated inflammation is implicated in disease progression and worsening of patients' QoL. Conventional anticancer therapeutics while selectively eliminating cancerous cells, are evaded by stem cell-like cells, and associated with varying degrees of adverse effects, thus reducing patients' QoL. This necessitates novel therapeutic approaches with enhanced efficacy, minimal or no treatment-related adverse effects, and improved QoL in patients with cancer, especially those with metastatic/advance stage disease. Methods: Sequel to our team's previous publication, the present study explores probable effects of Astragalus polysaccharides (PG2) on cancer-related inflammatory landscape and known determinants of QoL, as well as the probable link between the two to provide mechanistic insight. In an exploratory double blind randomized controlled trial using patients with metastatic disease (n = 23), we comparatively evaluated the therapeutic efficacy of high (500 mg) or low (250 mg) dose PG2 administered intravenously (i.v.), with particular focus on its suggested anti-inflammatory function and the probable effect of same on QoL indices at baseline, then at weeks 4 and 8 post-PG2 treatment. Results: All 23 patients with metastatic disease treated with either low or high PG2 experienced reduced pain, nausea, vomiting, and fatigue, as well as better appetite and sleep, culminating in improved global QoL. This was most apparent in the high dose group, with significant co-suppression of pro-inflammatory interleukin (IL)-1ß, IL-4, IL-6, IL-13, IL-17, monocytes chemotactic protein (MCP)1, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), tumor growth factor (TGF)-ß1, interferon (IFN)-γ, and immune suppressors IL-10 and IL-12. Univariate and multivariate analyses revealed that IL-1ß, IL-13 and GM-CSF are independent prognosticators of improved QoL. Conclusion: This proof-of-concept study provides premier evidence of functional association between PG2 anti-inflammatory effects and improved QoL in patients with advanced stage cancers, laying the groundwork for future larger cohort blinded controlled trials to establish the efficacy of PG2 as adjuvant anticancer therapy in metastatic or advanced stage clinical settings.

13.
J Enzyme Inhib Med Chem ; 34(1): 1287-1297, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31288582

RESUMO

Inhibition of NF-κB signalling has been demonstrated as a therapeutic option in treating inflammatory diseases and cancers. Herein, we synthesized novel dissymmetric 3,5-bis(arylidene)-4-piperidones (BAPs, 83-102) and characterized fully. MTT and ELISA assay were performed to screen the anti-hepatoma and anti-inflammation properties. 96 showed the most potential bioactivity. 96 could promote HepG2 apoptosis through up-regulating the expression of C-Caspase-3 and Bax, down-regulating the expression of Bcl-2, while markedly inhibit LPS or TNF-α-induced activation of NF-κB through both inhibiting the phosphorylation of IκBα and p65, and preventing the p65 nuclear translocation to exhibit both anti-hepatoma and anti-inflammatory activities. Molecular docking verified that simulated 96 can effectively bond to the active site of Bcl-2 and NF-κB/p65 proteins. 96 inhibited xenografts growth by reducing the expression of TNF-α and Bcl-2 in the tumour tissue. This study suggested that 96 could be developed as a potential multifunctional agent for treatment of inflammatory diseases and cancers.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Inflamação/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , NF-kappa B/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular
14.
Cell Biochem Biophys ; 77(3): 253-260, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31131438

RESUMO

Phospholipase A and acyltransferase 4 (PLAAT4) is a member of the HREV107 tumor suppressor gene family. The expression of PLAAT4 has been shown to induce cell death; however, the underlying mechanism remains unknown. Here, we found that RPLP0, a ribosomal protein, can interact with PLAAT4, as determined by yeast two-hybrid screening, coimmunoprecipitation, and colocalization. The level of RPLP0 was suppressed in HtTA cervical cancer cells expressing PLAAT4. In PLAAT4-expressing or RPLP0-silenced cells, decreased cell viability and cell proliferation combined with increased cell death were observed. Furthermore, the levels of cell cycle-associated proteins and anti-apoptotic proteins decreased in PLAAT4-expressing or RPLP0-silenced cells. Similar patterns of cell viability and expression levels of cell-cycle-associated proteins and apoptosis-related proteins were observed in PLAAT4-expressing and RPLP0-knockdown cells, indicating that RPLP0 deficiency might be involved in PLAAT4-mediated growth inhibition and cellular apoptosis.


Assuntos
Apoptose , Pontos de Checagem do Ciclo Celular , Receptores do Ácido Retinoico/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Células HeLa , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores do Ácido Retinoico/antagonistas & inibidores , Proteínas Ribossômicas/antagonistas & inibidores , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo
15.
J Exp Clin Cancer Res ; 38(1): 180, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036057

RESUMO

BACKGROUND: Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells. METHODS: This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays. RESULTS: In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells. CONCLUSION: In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Oxirredutases Intramoleculares/genética , Neoplasias Pulmonares/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/genética , Receptores Virais/genética , Células A549 , Animais , Carcinogênese/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Dasatinibe/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genética
16.
J Clin Med ; 8(4)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027263

RESUMO

Negative pressure ventilation (NPV), when used as an adjuvant to pulmonary rehabilitation, improves lung function, increases exercise capacity, and reduces exacerbations. The aim of this study was to determine whether maintenance NPV improves long-term clinical outcomes and reduces mortality in patients with chronic obstructive pulmonary disease (COPD). Between 2003 and 2009, 341 patients were treated for COPD either with or without hospital-based NPV. We measured forced expiratory volume in one second (FEV1), 6-min walking distance (6MWD), and oxygen saturation by pulse oximetry (SpO2) during a 6-min walk test (6MWT) every 3-6 months. Desaturation (D) during the 6MWT was defined as a reduction in SpO2 of ≥10% from baseline. The NPV group had a better survival outcome than the Non-NPV group. The 8-year survival probabilities for the NPV and Non-NPV groups were 60% and 20%, respectively (p < 0.01). Baseline desaturation was a significant risk factor for death, and the risk of death increased with desaturation severity (SpO2 80~89: hazard ratios (HR) 2.7, 95% confidence interval (CI) 1.4-5.3; SpO2 < 80: HR 3.1, 95% CI 1.3-7.4). The NPV group had a slower decline in lung function and 6MWD. The NPV + D and Non-NPV+D had a threefold and fourfold increase in the risks of all-cause mortality compared with the NPV-ND, respectively. Maintenance non-invasive NPV reduced long-term mortality in COPD patients. The desaturating COPD patients had an increased mortality risk compared with non-desaturating COPD patients.

17.
Biomed Res Int ; 2019: 6360503, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30886861

RESUMO

Ebastine is a second-generation histamine H1 receptor antagonist that is used to attenuate allergic inflammation. Ebastine has also shown to affect hair loss; however, the immunoregulatory effect of ebastine cannot completely exclude the possibility of spontaneous hair regrowth in ebastine-treated mice. In this study, we examined the effects of ebastine on the growth of human follicle dermal papilla cells (HFDPC) using a WST-1 cell proliferation assay and a bromodeoxyuridine incorporation assay. Ebastine was shown to significantly increase the proliferation of HFDPC. The expression levels of cell-cycle regulatory proteins and an antiapoptotic protein were increased in ebastine-treated HFDPC. Furthermore, elevated expression levels of phospho-AKT and phospho-p44/42 extracellular signal-regulated kinase (ERK) were observed in ebastine-treated HFDPC. Ebastine-mediated HFDPC growth was completely reversed by blocking ERK kinase. The results from our present study suggest that the regulation of HFDPC proliferation by ebastine might be directly involved in hair regrowth through the ERK signaling pathway.


Assuntos
Alopecia/genética , Butirofenonas/farmacologia , Folículo Piloso/crescimento & desenvolvimento , Proteína Quinase 3 Ativada por Mitógeno/genética , Piperidinas/farmacologia , Alopecia/tratamento farmacológico , Alopecia/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Derme/efeitos dos fármacos , Derme/crescimento & desenvolvimento , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Cabelo/efeitos dos fármacos , Cabelo/crescimento & desenvolvimento , Folículo Piloso/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-akt/genética
18.
BMC Pulm Med ; 19(1): 28, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30717716

RESUMO

BACKGROUND: Osteoporosis is a common comorbidity in non-cystic fibrosis (non-CF) bronchiectasis patients. We determined whether desaturation during 6-min walk test (6MWT) can be a predictor for osteoporosis risk. METHODS: This was a retrospective cross-sectional study. Sixty-six non-CF bronchiectasis patients were enrolled. Lung function, walking distance, the lowest oxygen saturation (SpO2), the fall in SpO2 (ΔSpO2), and the distance-saturation product (DSP) were determined during the 6MWT. Desaturators (n = 45) were defined as those with ΔSpO2 > 10% or the lowest SpO2 < 88%. Bone mineral density (BMD) was determined through dual-energy X-ray absorptiometry. The severity of non-CF bronchiectasis was evaluated using high-resolution computed tomography. RESULTS: Osteoporosis was evident in more desaturators (82%) than non-desaturators (43%, p < 0.01). BMD at the level of the femoral neck was significantly lower in desaturators than in non-desaturators (- 3.6 ± 1.1 vs. - 2.4 ± 0.9, p < 0.01). BMD was correlated positively with the lowest SpO2 and negatively with ΔSpO2 and severe exacerbations. In multivariate linear regression analysis, desaturation during 6MWT was the most significant predictive factor for osteoporosis (95% confidence interval - 1.60 to - 0.26, p = 0.01). Other risk factors included old age, low body mass index and severe exacerbation. CONCLUSIONS: Exertional desaturation during the 6MWT was a significant predictive factor for osteoporosis in Asian non-CF bronchiectasis patients. The 6MWT may be useful in identifying the osteoporotic phenotype of non-CF bronchiectasis and increasing clinician awareness to promote early intervention.


Assuntos
Bronquiectasia/fisiopatologia , Osteoporose/diagnóstico , Oxigênio/sangue , Teste de Caminhada , Idoso , Densidade Óssea , Bronquiectasia/complicações , Comorbidade , Estudos Transversais , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Osteoporose/complicações , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Taiwan , Tomografia Computadorizada por Raios X
19.
Eur J Med Chem ; 167: 187-199, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771605

RESUMO

To get new anti-hepatoma agents with anti-inflammatory activity and hypotoxicity, a series of dissymmetric pyridyl-substituted 3,5-bis(arylidene)-4-piperidones (BAPs, 25-82) were designed and synthesized. Many of them exhibited potential anti-hepatoma properties against human hepatocellular carcinoma cell lines (HepG2, QGY-7703, SMMC-7721) and hypotoxicity for human normal heptical cell line (HHL-5, LO2), and prominently inhibited lipopolysaccharides (LPS) induced IL-6, TNF-α secretion to exert its anti-inflammatory effect. Combining the data of cytotoxicity, cytocompatibility and anti-inflammatory activity, 3-pyridyl and -CF3 substituted 67 may be the potential anti-hepatoma agent. 67 effectively promoted cell apoptosis through up-regulating cleaved caspase-3 and Bax expression and down-regulating Bcl-2 expression. Furthermore, 67 prominently inhibited NF-κB pathway activation by blocking the phosphorylation of IκBα, p65 and the nuclear translocation of NF-κB induced by TNF-α and LPS. In addition, 67 could reasonably bind to the active site of Bcl-2 and NF-κB/p65 protein proved by Molecular docking analyses. Moreover, 67 significantly suppressed the growth and inflammatory response of HepG2 xenografts in nude mice and was relatively nontoxic to mice. These results suggest that 67 may be effective and hypotoxicity anti-hepatoma agent for the clinical treatment of liver cancers.


Assuntos
Antineoplásicos/síntese química , Neoplasias Hepáticas Experimentais/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Piperidonas/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Xenoenxertos , Humanos , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Piperidonas/síntese química , Relação Estrutura-Atividade
20.
Rhinology ; 57(1): 57-66, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30609423

RESUMO

Background: Cigarette smoke have adverse effects in the control of asthma and chronic rhinosinusitis (CRS). Interleukin (IL)-17A, the signature cytokine of helper T 17 cells and group 3 innate lymphoid cells (ILC3), has been reported to link with resistance to therapy in airway inflammation. This study aimed to investigate the impact of cigarette smoking and IL-17A activation on the clinical outcomes of asthmatic patients with chronic rhinosinusitis. Methods: 33 patients with CRS and asthma, including 15 smokers and 18 non-smokers, and 7 asthmatic patients without CRS and smoking were prospectively recruited. The Sino-Nasal Outcome Test-22 and Asthma Control Test were used to evaluate sinonasal symptoms and the level of asthma control, respectively. Real-time PCR and immunostaining were applied to evaluate the expression levels of IL-17A and associated immunological factors on surgically-obtained nasal tissues. Results: Nasal surgery improved both sinonasal symptoms and asthma control. Compared to non-smokers, smokers showed poorer improvement in asthma control. The expression of IL-17A, IL-22, aryl hydrocarbon receptor (AhR), and ILC3 was increased in the nasal tissues of smokers with asthma and CRS. The expression of IL-17A mRNA was correlated with that of AhR and with positive nuclear AhR-AhR nuclear translocator staining cells, and that of cyclooxygenase-2 enzyme (COX-2). ILC3 cells were associated with IL-17A, IL-22, AhR, and COX-2 mRNA expression. Conclusions: Cigarette smoking was related to lesser improvement in asthma control after nasal surgery and to IL-17A activation in the nasal tissues of patients with inflammatory airways.


Assuntos
Asma , Interleucina-17 , Rinite , Sinusite , Humanos , Interleucina-17/metabolismo , Rinite/diagnóstico , Rinite/etiologia , Fumar
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