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1.
Heliyon ; 10(7): e29312, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38623210

RESUMO

This research dives into the intricate immune landscape of head and neck cancer (HNC), with a keen focus on the roles of specific immune cell subpopulations and their linked genes. We used tumour RNA-seq (in-house cohort: n = 192, TCGA-HNSC: n = 546) and Mendelian randomization to pinpoint key SNPs in immune cells that have a causal connection to HNC. Our discoveries unveil a spectrum of tumour immune phenotypes that either offer protection against or increase the risk of HNC. We underscore the therapeutic promise of Complement C3d Receptor 2 (CR2), a gene closely tied to immune cells, with its increased expression in tumour tissues linked to a more favourable prognosis. This is correlated with heightened immune pathway activity, stronger resistance to radiochemotherapy, and improved immunotherapy responses. Our research emphasises the pivotal role of CR2 in immune regulation and the significance of immune cells in tumour progression, highlighting the potential of CR2-targeted therapeutic interventions.

2.
Oncologist ; 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38625619

RESUMO

BACKGROUND: Few studies have assessed the comprehensive associations among comorbid diseases in elderly patients with nasopharyngeal carcinoma (NPC). This study sought to identify potential comorbidity patterns and explore the relationship of comorbidity patterns with the mortality risk in elderly patients with NPC. METHODS: A total of 452 elderly patients with NPC were enrolled in the study. The network analysis and latent class analysis were applied to mine comorbidity patterns. Propensity score matching was used for adjusting confounders. A restricted cubic spline model was used to analyze the nonlinear association between age and the risk of all-cause mortality. RESULTS: We identified 2 comorbidity patterns, metabolic disease-related comorbidity (MDRC) and organ disease-related comorbidity (ODRC) in elderly patients with NPC. Patients in MDRC showed a significantly higher risk of all-cause mortality (71.41% vs 87.97%, HR 1.819 [95% CI, 1.106-2.994], P = .031) and locoregional relapse (68.73% vs 80.88%, HR 1.689 [95% CI, 1.055-2.704], P = .042). Moreover, in patients with MDRC pattern, we observed an intriguing inverted S-shaped relationship between age and all-cause mortality among patients aged 68 years and older. The risk of mortality up perpetually with age increasing in ODRC group, specifically within the age range of 68-77 years (HR 4.371, 1.958-9.757). CONCLUSION: Our study shed light on the potential comorbidity patterns in elderly patients with NPC, thereby providing valuable insights into the development of comprehensive health management strategies for this specific population.

3.
Sci Rep ; 14(1): 7686, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561379

RESUMO

Parotid mucoepidermoid carcinoma (P-MEC) is a significant histopathological subtype of salivary gland cancer with inherent heterogeneity and complexity. Existing clinical models inadequately offer personalized treatment options for patients. In response, we assessed the efficacy of four machine learning algorithms vis-à-vis traditional analysis in forecasting the overall survival (OS) of P-MEC patients. Using the SEER database, we analyzed data from 882 postoperative P-MEC patients (stages I-IVA). Single-factor Cox regression and four machine learning techniques (random forest, LASSO, XGBoost, best subset regression) were employed for variable selection. The optimal model was derived via stepwise backward regression, Akaike Information Criterion (AIC), and Area Under the Curve (AUC). Bootstrap resampling facilitated internal validation, while prediction accuracy was gauged through C-index, time-dependent ROC curve, and calibration curve. The model's clinical relevance was ascertained using decision curve analysis (DCA). The study found 3-, 5-, and 10-year OS rates of 0.887, 0.841, and 0.753, respectively. XGBoost, BSR, and LASSO stood out in predictive efficacy, identifying seven key prognostic factors including age, pathological grade, T stage, N stage, radiation therapy, chemotherapy, and marital status. A subsequent nomogram revealed a C-index of 0.8499 (3-year), 0.8557 (5-year), and 0.8375 (10-year) and AUC values of 0.8670, 0.8879, and 0.8767, respectively. The model also highlighted the clinical significance of postoperative radiotherapy across varying risk levels. Our prognostic model, grounded in machine learning, surpasses traditional models in prediction and offer superior visualization of variable importance.


Assuntos
Carcinoma Mucoepidermoide , Neoplasias Parotídeas , Humanos , Nomogramas , Carcinoma Mucoepidermoide/cirurgia , Neoplasias Parotídeas/cirurgia , Algoritmos , Aprendizado de Máquina
4.
Neuroscience ; 524: 94-107, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37295596

RESUMO

Understanding the role and mechanism of astrocytes in inflammation and oxidative response is crucial for developing therapeutic strategies to reduce inflammation and oxidative injury in cerebral ischemia-reperfusion injury (CIRI). In this study, we investigated the regulatory effects of phosphoglycerate kinase 1 (PGK1) on inflammation and oxidative response after CIRI in male adult Sprague-Dawley (SD) rats and using primary astrocytes obtained from neonatal SD rats, and explored its related mechanisms. We established a rat model of middle cerebral artery occlusion-reperfusion (MCAO/R) by suture occlusion, and an oxygen-glucose deprivation/reoxygenation model of astrocytes using oxygen-free, glucose-free, and serum-free cultures. AAV8-PGK1-GFP was injected into the left ventricle 24 h before modeling. Real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, co-immunoprecipitation (CoIP) assay, fluorescence in situ hybridization (FISH), and western blotting were used to elucidate the in-depth mechanisms of PGK1 in CIRI. PGK1 overexpression significantly exacerbated neurological deficits, increased cerebral infarct volume, and aggravated nerve cell injury in rats after MCAO/R. Using FISH and CoIP assays, we verified the localization of PGK1 and Nrf2 in primary astrocytes. Further rescue experiments showed that Nrf2 knockdown eliminated the protective effect of CBR-470-1 (a PGK1 inhibitor) on CIRI. Lastly, we confirmed that PGK1 aggravates CIRI by inhibiting the Nrf2/ARE pathway. In conclusion, our findings suggest that inhibiting PGK1 attenuates CIRI by reducing the release of inflammatory and oxidative factors from astrocytes by activating the Nrf2/ARE signaling pathway.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Fosfoglicerato Quinase/metabolismo , Fosfoglicerato Quinase/farmacologia , Doenças Neuroinflamatórias , Fator 2 Relacionado a NF-E2/metabolismo , Hibridização in Situ Fluorescente , Estresse Oxidativo , Infarto da Artéria Cerebral Média/metabolismo , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/metabolismo
5.
Food Chem ; 404(Pt A): 134608, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36272301

RESUMO

Our previous studies have confirmed oligopeptides could be meaningful to tea taste and biofunction. As the total content of oligopeptide among different tea types were varied. It is a natural speculation that certain tea processing step could be vital for oligopeptides enrichment. In current study, five types of traditional Chinese tea were produced from the same batch of fresh leaves. Step processing samples were acquired through which to profile the oligopeptides and free amio acids composition change during tea processed. As a result, firstly, withering was the vital step for oligopeptide enrichment, followed by fermentation, yellowing and drying. Secondly, as the enrichment of oligopeptides was often accompanied by the increase of protein amino acids, suggesting certain proteins degradation in fresh leaves could be the main source of oligopeptides. Thirdly, a total of 166 abundant oligopeptides were screened out, through which 14 high degradation protein were also located by protomic approaching.


Assuntos
Camellia sinensis , Chá , Chá/química , Aminoácidos/análise , Fermentação , Camellia sinensis/química , Folhas de Planta/química , Oligopeptídeos/metabolismo
6.
Bioorg Chem ; 128: 106100, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35988518

RESUMO

Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the ß-amyloid (Aß) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aß deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aß levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.


Assuntos
Doença de Alzheimer , Melatonina , Doenças Neurodegenerativas , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Quelantes/farmacologia , Modelos Animais de Doenças , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Transgênicos , Trientina/uso terapêutico
7.
Org Biomol Chem ; 20(34): 6831-6843, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-35968752

RESUMO

Three monoterpene alkaloids amycolasporin A and (±) amycolasporins B and C have been synthesized for the first time from commercially available materials in yields of 31%, 14% and 21%, respectively. Their six analogues (18, 19, 30a and 30d-30f) were synthesized through a similar protocol. Meanwhile, the antibacterial activity of all synthesized molecules was evaluated, showing different levels of bioactivity. Among them, analogue 30d was screened as the most effective antibacterial candidate against E. coli (MIC value, 12.5 µg mL-1) and S. aureus (MIC value, 12.5 µg mL-1). Further investigation showed that 30d obviously inhibited biofilm formation and disrupted the preformed biofilm of E. coli and S. aureus by promoting intracellular ROS release.


Assuntos
Antibacterianos , Staphylococcus aureus , Antibacterianos/farmacologia , Biofilmes , Escherichia coli , Testes de Sensibilidade Microbiana
8.
Food Chem ; 378: 132130, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35033704

RESUMO

Peptides with different lengths or amino sequences could have specific tastes or bio-activities. So far, either the quantity or pattern differences of peptide among various of teas were unknown. Here, firstly, we developed a method for tea oligopeptide quantification and made comparison of their contents. Secondly, we applied ultra-high performance liquid chromatography coupled with quadrupole-orbitrap ultra-high resolution mass spectrometry (UHPLC-Quadrupole-Orbitrap-UHRMS) to sequence oligopeptides. As a result, the total amount of oligopeptides in white tea and dark tea were higher, followed by black tea and green tea, finally with oolong tea. It suggested that withering which undergoes with endogenous protease and post-fermented that undergoes with a participation of exotic micro-organisms were key in oligopeptide enrichment. Thirdly, a total of 902 abundant identified peptides, most of which were tripeptide, tetrapeptide, pentapeptide, and hexapeptide were screened against several existing peptide databases. There were a series of taste peptides and bio-active peptides existing.


Assuntos
Oligopeptídeos , Chá , Cromatografia Líquida de Alta Pressão , Fermentação , Espectrometria de Massas
9.
J Med Chem ; 64(9): 6008-6020, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33860662

RESUMO

Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure-activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3-kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.


Assuntos
Desenho de Fármacos , Terapia de Alvo Molecular , Fenóis/síntese química , Fenóis/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Fenóis/química , Fenóis/uso terapêutico , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
10.
Bioorg Chem ; 111: 104898, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33894428

RESUMO

Violacin A, a chromanone derivative, isolated from a fermentation broth of Streptomyces violaceoruber, has excellent anti-inflammatory potential. Herein, a biogenetically modeled approach to synthesize violacin A and twenty-five analogues was described, which involved the preparation of aromatic polyketide precursor through Claisen condensation and its spontaneous cyclization. The inhibitory effect on nitric oxide (NO) production of all synthetic molecules was evaluated by lipopolysaccharide (LPS)-induced Raw264.7 cells. The results revealed that introduction of aliphatic amine moieties on C-7 obviously improved the anti-inflammation effect of violacin A, and also the aromatic ether instead of ketone group at side chain was favorable to increase the activity. Among them, analogue 7a and 16d were screened as the most effective anti-inflammatory candidates. Molecular mechanism research revealed that 7a and 16d acquired anti-inflammatory ability due to the inhibition of NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Materiais Biomiméticos/farmacologia , Ciclotídeos/farmacologia , NF-kappa B/antagonistas & inibidores , Óxido Nítrico/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Ciclotídeos/síntese química , Ciclotídeos/química , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade
11.
Molecules ; 25(2)2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31963359

RESUMO

Chinese jasmine tea is a type of flower-scented tea, which is produced by mixing green tea with the Jasminum sambac flower repeatedly. Both the total amount and composition of volatiles absorbed from the Jasminum sambac flower are mostly responsible for its sensory quality grade. This study aims to compare volatile organic compound (VOC) differences in authoritative jasmine tea grade samples. Automatic thermal desorption-gas-chromatography-mass spectrometry (ATD-GC-MS) and electronic nose (E-nose), followed by multivariate data analysis is conducted. Consequently, specific VOCs with a positive or negative correlation to the grades are screened out. Partial least squares-discriminant analysis (PLS-DA) and hierarchical cluster analysis (HCA) show a satisfactory discriminant effect on rank. It is intriguing to find that the E-nose is good at distinguishing the grade difference caused by VOC concentrations but is deficient in identifying essential aromas that attribute to the unique characteristics of excellent grade jasmine tea.


Assuntos
Nariz Eletrônico , Cromatografia Gasosa-Espectrometria de Massas , Jasminum/química , Chá/química , Compostos Orgânicos Voláteis/química , Metabolômica/métodos , Análise Multivariada , Compostos Orgânicos Voláteis/análise
12.
Bioorg Chem ; 94: 103420, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718890

RESUMO

A concise total synthesis of an exceedingly potent anti-inflammatory agent violacin A as well as the preparation of thirty analogues of this lead from commercially available orcinol are described. Highlights of our synthetic efforts involve Friedel-Crafts acylation, the regioselective etherification and esterification of phenolic hydroxyl groups, and Baker-Venkatamaran rearrangement to form basic skeleton of violacin A. The deprotection reaction with Pd-catalytic was involved to avoid the elimination of the hemiacetal hydroxyl at C2. In addition, all synthetic compounds were screened for anti-inflammatory activity against nitric oxide (NO) production using lipopolysaccharide (LPS)-induced Raw264.7 cells. A range of violacin A derivatives 11b, 11d, 11f, 12e, 12g, 13g, 17d-g exhibited stronger anti-inflammatory effect than that of violacin A. Notably, halogeno-benzyloxy substituent at C-7 were favourable for anti-inflammatory activities of violacin A derivatives. Additionally, Western blot results indicated halogeno-benzyloxy derivatives inhibited pro-inflammatory cytokines releases correlated with the suppression of NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ciclotídeos/química , Ciclotídeos/síntese química , Anti-Inflamatórios/farmacologia , Humanos , Estrutura Molecular
13.
Bioorg Med Chem ; 26(23-24): 6035-6049, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442507

RESUMO

Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5-phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 µg/mL, respectively). Furthermore, compounds 4n and 4r presented better antifungal activity against Aspergillus fumigatus with 12.5 µg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH2CH2N- had an important effect on the antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic fungal threonyl-tRNA synthetase (ThrRS).


Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida/efeitos dos fármacos , Desenho de Fármacos , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Álcoois Graxos/síntese química , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
14.
Oncotarget ; 6(19): 17675-84, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25970778

RESUMO

China has different ethnic minorities that establish their own medical systems and practice experience for thousand years, thereafter named Chinese Ethnic Minority Traditional Drugs (CEMTDs) (http://www.cemtdd.com/index.html). Since many compounds from CEMTDs have been reported to perturb human's dysfunction network and restore human normal physiological conditions, the relationships amongst a series of compounds from specific herbs, their targets and relevant diseases have become our main focus in CEMTD modernization. Herein, we have constructed the first Chinese Ethnic Minority Traditional Drug Database (CEMTDD) mainly from Xinjiang Uygur Autonomous Region (XUAR), retrieving CEMTD-related information from different resources. CEMTDD contains about 621 herbs, 4, 060 compounds, 2, 163 targets and 210 diseases, among which most of herbs can be applied into gerontology therapy including inflammation, cardiovascular disease and neurodegenerative disease. Gerontology is highly occurred in XUAR, and has abundant experience in treating such diseases, which may benefit for developing a new gerontology therapeutic strategy. CEMTDD displays networks for intricate relationships between CEMTDs and treated diseases, as well as the interrelations between active compounds and action targets, which may shed new light on the combination therapy of CEMTDs and further understanding of their herb molecular mechanisms for better modernized utilizations of CEMTDs, especially in gerontology.


Assuntos
Bases de Dados Factuais , Medicamentos de Ervas Chinesas , Humanos , Medicina Tradicional Chinesa
15.
J Cancer Res Clin Oncol ; 138(5): 763-74, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22270966

RESUMO

AIMS: The aim of this study was (a) to determine the role of micro-223 (miR-223) in gastric cancer and (b) to elucidate its regulatory mechanism on the FBXW7/hCdc4 gene. MATERIALS AND METHODS: Artificial miR-223 and control oligonucleotide was transfected into gastric cancer cell line SGC7901 by using Lipofectamine2000. Apoptosis of miR-223 group and control group cells was analyzed by flow cytometry, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and colony formation assays were performed to detect the cell viability, to survey migration of miR-223 group and control group cells; scratch wound-healing motility assays, Transwell Assay, and Western blot test were performed to measure the variance of hFBXW7. Luciferase Reporter Assay, which was done by pLUC-hFBXW7 WT-3'-UTR co-transfected with pLMP-hsa-miR-223 or pLMP plasmid (as control) into HEK293T cells, used to detect whether hFBXW7 is a direct target gene of miR-223. Gastric cancer cell line SGC7901 transfected with miR-223 or control oligonucleotide was resuspended in ECM gel and then was injected into the flank of nude mice, 4 weeks later, the nude mice were euthanized. The tumors were excised then were measured and weighted. SYBR-Green I-based real-time RT-PCR study was used to detect the level of miR-223 in 22 gastric cancer tissue and corresponding gastric mucosa tissues. Immunohistochemical method was applied to detect the protein of hFBXW7. RESULTS: Gastric cancer cell line SGC7901, transfected with miR-223, showed significant reduction in cellular apoptosis and increased proliferation and invasion in vitro. Similar results were found in tumorigenesis assays performed in nude mice. Moreover, 19 of 22 cancer tissue samples highly expressed miR-223, when compared with patient-matched normal gastric mucosa. Specifically, patients with lymph node metastasis or metastatic disease (M1) at an advanced pathological stage showed significantly higher expression of miR-223. FBXW7/hCdc4 protein (FBW7) levels in gastric cancer cases were inversely correlated with miR-223 expression. Overexpression of miR-223 in gastric cancer cell lines decreased FBW7 expression at the translational level and decreased FBXW7/hCdc4-driven luciferase-reporter activity. CONCLUSION: In summary, the data indicated that miR-223 targets FBXW7/hCdc4 expression at the post-transcriptional level and appears to regulate cellular apoptosis, proliferation, and invasion in gastric cancer. MiR-223 may serve as a novel therapeutic target in gastric cancer.


Assuntos
Adenocarcinoma/genética , Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/fisiologia , Neoplasias Gástricas/genética , Ubiquitina-Proteína Ligases/genética , Adenocarcinoma/patologia , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células , Proteína 7 com Repetições F-Box-WD , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , Oncogenes/fisiologia , Neoplasias Gástricas/patologia
16.
Chin Med J (Engl) ; 124(2): 268-72, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21362379

RESUMO

BACKGROUND: Semi-mature dendritic cells (DCs) may induce tolerance rather than immunity. However, little is known about the regulatory mechanism by which these DCs induce transplant tolerance. Myeloid differentiation factor 88 (MyD88) is a key adaptor of Toll-like receptor signaling, which plays a critical role in DC maturation. Activation of MyD88-silenced immature DCs results in the generation of semi-mature DCs. We explored the possibility of using these DCs to induce intestinal transplant tolerance in rats. METHODS: MyD88 expression was silenced in bone marrow DCs (F344 rats) using small interfering RNAs for 24 hours, at which point, lipopolysaccharide (LPS) was added to the culture for another 48 hours. These cells were analyzed for their in vitro and in vivo tolerizing capacities. RESULTS: Semi-mature DCs expressing moderate levels of MHC class II and low levels of co-stimulatory molecules were found to produce interleukin (IL)-10, while IL-12 production was decreased. In vitro co-culture with completely allogeneic T cells from Wistar rats led to a significant decrease in alloreactive T-cell responses. In vivo, the transfer of semi-mature DCs (1 × 10(6) cells) followed by the transplantation of fully mismatched intestinal grafts (F344 rats) led to significantly prolonged survival compared to rats receiving immature and mature DCs. Serum from semi-mature DC-treated rats contained lower concentrations of the pro-inflammatory cytokines IL-2 and interferon-γ 5 days after transplantation. CONCLUSION: Semi-mature DCs may promote inducible allograft tolerance and this study suggests a new strategy by which to facilitate the induction of transplant tolerance.


Assuntos
Células da Medula Óssea/citologia , Células Dendríticas/metabolismo , Intestinos/transplante , Fator 88 de Diferenciação Mieloide/metabolismo , Transplante Homólogo/métodos , Animais , Western Blotting , Proliferação de Células , Células Dendríticas/citologia , Ensaio de Imunoadsorção Enzimática , Masculino , Fator 88 de Diferenciação Mieloide/genética , Reação em Cadeia da Polimerase , Ratos , Ratos Endogâmicos F344 , Linfócitos T/metabolismo
17.
Anat Rec (Hoboken) ; 294(3): 527-32, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21284090

RESUMO

Resveratrol, a phytoalexin found in a range of plant products, may exert a variety of pharmacological activities. In this study, we investigated the effect of resveratrol on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo, and we found that the pretreatment with resveratrol can effectively protect mice against LPS-induced ALI. Mice were pretreated with 1 mg/kg resveratrol for 3 days before challenging with a dose of 15 mg/kg LPS. The histological result showed that resveratrol can suppress the edema, inflammatory cell infiltration, and alveolar structure damage of lungs in ALI mice, and a decrease in the lung W/D ratio was also observed in mice with resveratrol pretreatment. Additionally, resveratrol markedly decreased the production of inflammatory cytokines, including IL-1ß and MIP-1α and prevented the release of nitric oxide (NO) through inhibiting the expression of inducible NO synthase in lung tissues. Furthermore, the pretreatment with resveratrol suppressed the nuclear translocation of NF-κB in lung tissues, which may be partly responsible for its effect on the ALI. In conclusion, the results presented here may suggest resveratrol as a potential therapeutic agent for treating ALI in the future.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Lipopolissacarídeos/toxicidade , Estilbenos/uso terapêutico , Animais , Western Blotting , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Modelos Animais de Doenças , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , Resveratrol , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
J Surg Res ; 171(2): 826-32, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20828738

RESUMO

BACKGROUND: Dendritic cells (DCs) secrete exosomes bearing major histocompatibility complex I and II (MHC I /II) and co-stimulatory molecules, and play a critical role in immune regulation. Because immature DCs can induce T-cell tolerance in vitro and in vivo, we explored the possibility of using exosomes derived from immature DCs (imDex) for the induction of intestinal transplant tolerance in rats. MATERIALS AND METHODS: ImDex were purified from F344 rat bone marrow immature DCs. The tolerizing capacities of imDex were analyzed in vitro and in vivo using a F344-to-Wistar intestinal transplantation model. RESULTS: In the context of a moderate level of MHC class II and a low co-stimulatory level expression, imDex significantly suppressed the alloreactive T-cell response with an increase in IL-10 in vitro. In vivo injection of the lower dose (20 µg) of donor (but not recipient) imDex can significantly prolong the survival of intestinal allografts. This effect was accompanied by a decrease in the anti-donor cellular response, with a significant increase in IL-10. The CD4+CD25+T cells percentage and FOXP3mRNA expression in splenic T-cells were also significantly increased in imDex treatment recipients at five days after transplantation. CONCLUSIONS: The results suggest that imDex can prolong the intestinal allograft survival and may be a potential strategy to facilitate induction of transplant tolerance.


Assuntos
Células da Medula Óssea/imunologia , Células Dendríticas/imunologia , Exossomos/imunologia , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica/imunologia , Intestinos/transplante , Doença Aguda , Animais , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Ratos , Ratos Endogâmicos F344 , Baço/citologia , Baço/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo
19.
Scand J Gastroenterol ; 45(10): 1168-77, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20469967

RESUMO

OBJECTIVE: Inflammatory bowel disease (IBD), which mainly refers to Crohn's disease and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract. Recent reports have demonstrated that exosomes derived from interleukin-10 (IL-10)-treated bone marrow-derived dendritic cells (DCs) can reduce the incidence and severity of established collagen-induced arthritis (CIA) in mice. Based on the essential role of IL-10 in the development of normal mucosal immunity, we investigated whether exosomes derived from DCs treated with IL-10 (known as IL-10-exosomes) can suppress the trinitrobenzene sulfonic acid (TNBS)-induced colitis. MATERIAL AND METHODS: We used the rat TNBS-induced colitis model to address the therapeutic potential of IL-10-exosomes in vivo. More specifically, a rectal enema of TNBS was administered to Wistar rats, and IL-10-exosomes were injected intraperitoneally on Day 3. RESULTS: In the context of a high level of major histocompatibility complex class II (MHC II) and a low level of co-stimulatory molecule and membrane-bound IL-10 expression, IL-10-exosomes treatment substantially reduced all analyzed clinical, macroscopic, and histopathologic parameters of TNBS-induced colitis. The therapeutic effects of IL-10-exosomes were associated with a down-regulation mRNA expression of IL-2, IFN-γ and TNF-α in colon tissues. Importantly, treatment with IL-10-exosomes resulted in a pronounced up-regulation of IL-10mRNA expression in colon tissues and regulatory T cells (Tregs) in Colonic lamina propria. CONCLUSIONS: The results suggest that IL-10-exosomes treatment can suppress acute TNBS-induced colitis and may offer a promising new therapeutic strategy for IBD.


Assuntos
Colite/imunologia , Colite/terapia , Células Dendríticas , Exossomos/imunologia , Interleucina-10/imunologia , Animais , Colite/induzido quimicamente , Colite/genética , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/terapia , Interferon gama/efeitos dos fármacos , Interleucina-2/biossíntese , Masculino , Mucosa/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Wistar , Linfócitos T/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/efeitos dos fármacos
20.
Cancer Biol Ther ; 9(12): 1000-7, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20364107

RESUMO

BACKGROUND: Aquaporins (AQPs) are expressed in many different tumor cell types in human. New evidence for the involvement of AQPs in cell migration and proliferation adds AQPs to an expanding list of effectors in tumor biology. AIMS: The aim of this study was to investigate whether AQP3 expression in the human gastric carcinoma cell lines, AGS and SGC7901, enhances cell migration and proliferation. RESULTS: Here, we showed that AQP3 is expressed in the human gastric cancer cell lines, AGS and SGC7901. The hEGF induced AQP3 expression in a time- and dose-dependent manner and increased gastric cancer cell migration and proliferation. AQP3 knockdown by siRNA inhibited hEGF-induced AQP3 expression and thus cell migration and proliferation. Furthermore, a mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126 inhibited hEGF-induced AQP3 expression and cell migration or proliferation. METHODS: Cultured AGS or SGC7901 cells were treated with human epidermal growth factor (hEGF) and subjected to cell migration assay and cell proliferation assay. The expression or activation level of proteins was analyzed by western blot. AQP3 knockdown was obtained by small interfering (si)RNA. CONCLUSIONS: Collectively, our findings provide for the first time that AQP3 plays a critical role in hEGF-induced cancer cell migration and proliferation and that hEGF induces AQP3 expression via ERK signal transduction pathways. These finds provide evidence for a novel role of AQP3 in human gastric carcinoma as a potentially important determinant of tumor growth and spread.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Aquaporina 3/metabolismo , Fator de Crescimento Epidérmico/fisiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Aquaporina 3/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células , Humanos , Sistema de Sinalização das MAP Quinases
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