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1.
Anticancer Res ; 39(10): 5623-5630, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570459

RESUMO

BACKGROUND: This study aimed to investigate p16 and COX2 expression in oropharyngeal squamous cell carcinoma (OPSCC), and evaluate the prognostic role of COX2 expression under the new TNM classification. MATERIALS AND METHODS: Biopsy specimens obtained from 75 patients with OPSCC were stained for p16 and COX2 expression immunohistochemically. The results and clinical records were analyzed retrospectively. RESULTS: Fifty-nine patients (79%) were positive for p16. COX2 expression was correlated with poor relapse-free survival in patients overall, and in p16-positive patients. Smoking was positively associated with COX2 expression. Moreover, both positive COX2 expression and anterior wall tumor subsite were independently correlated with lymph node metastasis, which was the only independent prognostic factor in p16-positive OPSCC. CONCLUSION: The p16-positive rate in this study was comparable with that in the USA and Europe, and higher than that in other Asian countries. COX2 expression might affect the prognosis of p16-positive OPSCC through promoting lymph node metastasis.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Metástase Linfática/genética , Metástase Linfática/patologia , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Ciclo-Oxigenase 2/genética , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
2.
Chem Biol Interact ; 311: 108790, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31400342

RESUMO

Preclinical assays play a key role in research in research on the neurobiology of pain and the development of novel analgesics. Drugs available for the treatment of inflammatory pain are not fully effective and show adverse effects. Thus, we investigated the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of bis(3-amino-2-pyridine) diselenide (BAPD), a new analgesic drug prototype. BAPD effects were investigated using nociception models induced by chemical (glutamate), immunologic (Freund's Complete Adjuvant - CFA) and thermal stimuli in Swiss mice. Mice were orally (p.o.) treated with BAPD (0.1-50 mg/kg) 30 min prior to the glutamate and hot-plate tests and a time-course (0.5 up to 8 h) of the antinociceptive effect of BAPD (50 mg/kg, p. o.) was evaluated in a CFA model. In the CFA model, BAPD effects on cyclooxygenase-2 (COX-2), tumor necrosis factor (TNFα) and interferon-γ (INF-γ) expression, myeloperoxidase (MPO) activity, oxidative (2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels) and histological parameters were evaluated. The safety of the compound (50 and 300 mg/kg, p. o.) was verified for 72 h. BAPD reduced the licking time induced by glutamate and caused an increase in latency response to thermal stimulus. Naloxone reversed the antinociceptive effect of BAPD. Paw edema formation induced by glutamate or CFA injection was reduced by BAPD. Mechanical hyperalgesia induced by CFA was attenuated by BAPD. BAPD did not protect against the increase in MPO activity and decrease of the 2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels induced by CFA. BAPD protected against histological alterations and reduction on the levels of gene expression COX-2 and INF-γ in the paw of mice exposed to CFA. BAPD was safe at the doses and time evaluated. BAPD exerts acute antinociceptive, anti-inflammatory and anti-hyperalgesic actions, suggesting that it may represent an alternative in the future development of new therapeutic strategies.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Interferon gama/metabolismo , Nociceptividade/efeitos dos fármacos , Receptores Opioides/metabolismo , Analgésicos/química , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2/genética , Edema/tratamento farmacológico , Edema/patologia , Comportamento Exploratório/efeitos dos fármacos , Pé/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glutâmico/farmacologia , Interferon gama/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Dor/tratamento farmacológico , Dor/patologia , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores Opioides/genética , Testes de Toxicidade Aguda , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Chem Biol Interact ; 311: 108786, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31401087

RESUMO

Naturally occurring oleanolic acid (OA) possesses a hepatoprotective activity and ability to inhibit proliferation of human hepatocellular carcinoma cells. Both properties might be related to its anti-inflammatory activity. Its low bioavailability justifies the search for more hydrophilic OA derivatives. The aim of this study was the design and synthesis of four novel OA oxime derivatives conjugated with succinic acid at the C-3 position of oleanane skeleton structure and evaluation of their effect on NF-κB and STATs expression and activation in HepG2 cells. The expression of NF-κB and cyclooxygenase-2 (COX-2), STAT5A/B and STAT3 with its target genes: BAX, BCL-XL and MYC was evaluated after 24 h treatment with tested compounds. The comparison of the levels of cytosolic and nuclear NF-κB subunits p50, p65 and STATs proteins was used as the measure of their activation. The results pointed out the 3-succinyloxyiminoolean-12-en-28-oic acid morpholide (SMAM) as the most potent modulator of NF-κB and STAT3. SMAM significantly reduced the expression and activation of NF-κB as well as its nuclear protein level of p65 subunit. This compound also reduced the expression and activation of STAT3 and STAT5A/B. Combined effect of SMAM on these transcription factors resulted in reduced expression of COX-2, MYC and anti-apoptotic BCL-XL genes. Simultaneously, the increased expression of pro-apoptotic BAX gene was observed. In the cells treated with 3-succinyloxyiminoolean-12-en-28-oic acid (SMAA) the increased expression of BAX was also found. The effects of 3-succinyloxyiminoolean-12-en-28-oic acid benzyl ester (SMAEB) and 3-succinyloxyiminoolean-12-en-28-oic acid methyl ester (SMAEM) were moderate and ambiguous in relation to the tested factors. Moreover, the coordinated action of SMAM on NF-κB and STAT3 confirms their close association in HepG2 cells. We conclude that SMAM efficiently downregulates the key elements of signaling pathways involved in inflammatory driven HCC. Thus, may be considered as a potential chemopreventive or therapeutic agent in this type of cancer.


Assuntos
NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Oximas/farmacologia , Fatores de Transcrição STAT/metabolismo , Ácido Succínico/química , Carcinoma Hepatocelular , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Hep G2 , Humanos , Neoplasias Hepáticas , NF-kappa B/genética , Oximas/química , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição STAT/genética , Transcrição Genética/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
4.
J Agric Food Chem ; 67(35): 9796-9804, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31393712

RESUMO

Overactivated microglia and persistent neuroinflammation hold an important role in the pathophysiology of neurodegenerative diseases. The extract of Lycoris chejuensis (CJ) and its active compound, 7-deoxy-trans-dihydronarciclasine (named E144), attenuated expressions of pro-inflammatory factors, including nitric oxide, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and interleukin 6, secreted by lipopolysaccharide-activated BV-2 microglial cells, as measured by an enzyme-linked immunosorbent assay or western blotting. In contrast, CJ extract and E144 promoted the secretion of the anti-inflammatory cytokine, interleukin 10. Moreover, we found that E144 attenuated the expression of TNF-α and COX-2 in the cerebral cortex of lipopolysaccharide-treated mice and/or T2576 transgenic mice as well as reduced the reactive immune cells visualized by ionized calcium-binding adaptor molecule 1. Our results suggest the possibility of E144 to serve as a potential anti-neuroinflammatory agent by preventing excess production of pro-inflammatory factors.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Isoquinolinas/administração & dosagem , Lycoris/química , Extratos Vegetais/administração & dosagem , Doença de Alzheimer/genética , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Isoquinolinas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
Cancer Invest ; 37(8): 327-338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31423851

RESUMO

Little is known about the endocannabinoid (eCB) system in squamous cell carcinoma of the oral tongue (SCCOT). Here we have investigated, at the mRNA level, expression of genes coding for the components of the eCB system in tumour and non-malignant samples from SCCOT patients. Expression of NAPEPLD and PLA2G4E, coding for eCB anabolic enzymes, was higher in the tumour tissue than in non-malignant tissue. Among genes coding for eCB catabolic enzymes, expression of MGLL was lower in tumour tissue while PTGS2 was increased. It is concluded that the eCB system may be dysfunctional in SCCOT.


Assuntos
Biomarcadores Tumorais/genética , Endocanabinoides/genética , RNA Mensageiro/genética , Transdução de Sinais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias da Língua/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclo-Oxigenase 2/genética , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fosfolipases A2 do Grupo IV/genética , Humanos , Masculino , Pessoa de Meia-Idade , Monoacilglicerol Lipases/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosfolipase D/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias da Língua/patologia , Adulto Jovem
6.
J Dairy Sci ; 102(9): 7707-7716, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31326176

RESUMO

Maillard reaction products formed from whey protein isolate (WPI) and sugar have been shown to have an anti-inflammatory effect in vitro. Here, we incubated WPI and galactose (GWA) in an aqueous solution at 65°C for 24 h to produce a glycated conjugate, which was then fermented using Lactobacillus gasseri 4M13 to obtain the fermented product (F-GWA). We demonstrated that F-GWA had an anti-inflammatory effect on lipopolysaccharide (LPS)-stimulated RAW264.7 cells. It reduced both LPS-stimulated nitric oxide production and LPS-stimulated increases in the gene expression levels of tumor necrosis factor-α and cyclooxygenase-2 in a dose-dependent manner. Furthermore, F-GWA inhibited the LPS-induced phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase, members of the mitogen-activated protein kinase family. The glycation process was evaluated by measuring fluorescence intensity and the furosine concentration during the Maillard reaction to form GWA. The protein modifications of WPI were analyzed using MALDI-TOF tandem mass spectrometry. We found that the combination of the Maillard reaction and L. gasseri 4M13 fermentation increased the prebiotic properties of GWA as well as organic acid production, compared with the nonreacted WPI and galactose.


Assuntos
Anti-Inflamatórios/farmacologia , Fermentação , Lactobacillus gasseri/metabolismo , Macrófagos/fisiologia , Reação de Maillard , Proteínas do Soro do Leite/química , Animais , Ciclo-Oxigenase 2/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Galactose/metabolismo , Expressão Gênica/efeitos dos fármacos , Produtos Finais de Glicação Avançada , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Fator de Necrose Tumoral alfa/genética , Proteínas do Soro do Leite/metabolismo
7.
J Microbiol Biotechnol ; 29(7): 1022-1032, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31216608

RESUMO

Probiotics are known to provide the host with immune-modulatory effects and are therefore of remarkable interest for therapeutic and prophylactic applications against various disorders, including inflammatory diseases. Weissella cibaria JW15 (JW15) has been reported to possess probiotic and antioxidant properties. However, the effect of JW15 on inflammatory responses has not yet been reported. Therefore, the objective of the current study was to evaluate the anti-inflammatory potential of JW15 against lipopolysaccharide (LPS) stimulation. The production of pro-inflammatory factors and the cellular signaling pathways following treatment with heat-killed JW15 was examined in LPS-induced RAW 264.7 cells. Treatment with heat-killed JW15 decreased nitric oxide and prostaglandin E2 production via downregulation of the inducible nitric oxide synthase and cyclooxygenase-2. In addition, treatment with heat-killed JW15 suppressed the expression of pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. The anti-inflammatory properties of treating with heat-killed JW15 were associated with mitogen-activated protein kinase signaling pathwaymediated suppression of nuclear factor-κB. These results indicated that JW15 possesses antiinflammatory potential and provide a molecular basis regarding the development of functional probiotic products.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Probióticos/farmacologia , Fator de Transcrição RelA/metabolismo , Weissella/fisiologia , Animais , Sobrevivência Celular , Ciclo-Oxigenase 2/genética , Citocinas/genética , Citocinas/metabolismo , Dinoprostona/metabolismo , Alimentos Fermentados/microbiologia , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
8.
Mar Drugs ; 17(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151271

RESUMO

In our previous study, a synthetic compound, (+)-(R,E)-6a1, that incorporated the key structures of anti-inflammatory algal metabolites and the endogenous peroxisome proliferator-activated receptor γ (PPAR-γ) ligand 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), exerted significant PPAR-γ transcriptional activity. Because PPAR-γ expressed in macrophages has been postulated as a negative regulator of inflammation, this study was designed to investigate the anti-inflammatory effect of the PPAR-γ agonist, (+)-(R,E)-6a1. Compound (+)-(R,E)-6a1 displayed in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-stimulated murine RAW264.7 macrophages. Compound (+)-(R,E)-6a1 suppressed the expression of proinflammatory factors, such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), possibly by the inhibition of the nuclear factor-κB (NF-κB) pathway. In macrophages, (+)-(R,E)-6a1 suppressed LPS-induced phosphorylation of NF-κB, inhibitor of NF-κB α (IκBα), and IκB kinase (IKK). These results indicated that PPAR-γ agonist, (+)-(R,E)-6a1, exerts anti-inflammatory activity via inhibition of the NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/agonistas , PPAR gama/antagonistas & inibidores , Prostaglandinas Sintéticas/farmacologia , Animais , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-6/genética , Lipopolissacarídeos , Camundongos , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7 , Rodófitas/química , Fator de Necrose Tumoral alfa/genética
9.
DNA Cell Biol ; 38(7): 670-677, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31188027

RESUMO

Cutis laxa represents a heterogeneous group of rare, inherited, or acquired connective tissue disorders with the common feature of loose and redundant skin with decreased elasticity. The skin of affected deer showed abnormal collagen fiber morphology. To identify the differentially expressed genes of the unusual localized skin laxity in sika deer, we performed transcriptome analysis in the affected and control sika deer. The transcriptome analysis showed 700 genes with significant differential expression in the affected skin as compared with normal skin. Pathway analysis revealed an enrichment of genes involved in tumor necrosis factor signaling, the extracellular matrix-receptor interaction, platelet activation, and Huntington's disease. A gene network was constructed, and the hub nodes such as PTGS2, THBS1, COL1A1, FOS, and NOS3 were found through PPI network analysis, which may contributed to the unusual localized skin laxity in sika deer. Abnormal expression patterns of genes during the development of the affected sika deer were successfully uncovered in the present study, which provides a reference for revealing the related mechanism underlying cutis laxa in sika deer and human beings.


Assuntos
Cútis Laxa/veterinária , Cervos/genética , Transcriptoma , Animais , Colágeno/genética , Colágeno/metabolismo , Cútis Laxa/genética , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Redes Reguladoras de Genes , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo
10.
Korean J Parasitol ; 57(2): 207-211, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31104416

RESUMO

Anisakiasis is a zoonotic disease induced by anisakid nematodes, and endoscopic inspection is used for a diagnosis or remedy for it. Anisakis simplex, Anisakis physeteris, and Pseudoterranova decipiens had been reported to be the major species causing human infections, particularly, in Japan. However, in Korea, recent studies strongly suggested that Anisakis pegreffii is the major species of human infections. To support this suggestion, we collected anisakid larvae (n=20) from 20 human patients who were undergone gastrointestinal endoscopy at a health check-up center in Korea, and molecular identification was performed on the larvae using PCR-RFLP analysis and gene sequencing of rDNA ITS regions and mtDNA cox2. In addition, anisakid larvae (n=53) collected from the sea eel (Astroconger myriaster) were also examined for comparison with those extracted from humans. The results showed that all human samples (100%) were identified as A. pegreffii, whereas 90.7% of the samples from the sea eel were A. pegreffii with the remaining 9.3% being Hysterothylacium aduncum. Our study confirmed that A. pegreffii is the predominant species causing human anisakiasis in Korea, and this seems to be due to the predominance of this larval type in the fish (sea eels) popularly consumed by the Korean people. The possibility of human infection with H. aduncum in Korea is also suggested.


Assuntos
Anisaquíase/diagnóstico , Anisakis/classificação , Anisakis/isolamento & purificação , Endoscopia Gastrointestinal/métodos , Técnicas de Diagnóstico Molecular/métodos , Adulto , Idoso , Animais , Anisaquíase/veterinária , Anisakis/genética , Ciclo-Oxigenase 2/genética , DNA Mitocondrial/química , DNA Mitocondrial/genética , DNA Espaçador Ribossômico/química , DNA Espaçador Ribossômico/genética , Enguias/parasitologia , Feminino , Doenças dos Peixes/parasitologia , Humanos , Larva/classificação , Larva/genética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , República da Coreia , Análise de Sequência de DNA
11.
Mol Med Rep ; 19(6): 4655-4662, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059003

RESUMO

Preeclampsia remains a major cause of maternal mortality and morbidity worldwide. It is generally accepted that the development of the placenta, including spiral artery remodelling, normal trophoblast cells function and maternal­fetal inflammation­immune interactions, is critical for the pathogenesis of preeclampsia. Several investigations have demonstrated that microRNAs (miRNAs/miRs) in the placenta may be potential molecular markers for diagnosis of preeclampsia. In the current study, the aim was to investigate the expression of miR­144­3p in the placenta of patients with preeclampsia and normal placentas, and to explore the potential target genes. miRNA microarray analysis was performed using three paired placentas (preeclampsia and normal) in order to find differential expression of miRNAs. Following this, miR­144­3p was selected as a differentially expressed miRNA and validated using in situ hybridization to determine the clinical significance in placentas with preeclampsia. A potential target gene of miR­144­3p, cyclooxygenase­2 (Cox­2), was identified by bioinformatics, luciferase reporter assay and western blotting. The expression of Cox­2 was also examined by immunohistochemical staining of samples of placenta from patients with preeclampsia and normal placenta. Western blot analysis was performed to investigate the effect of miR­144­3p on the expression of Cox­2 in HTR­8/SVneo cells in vitro. miR­144­3p was decreased in placentas from patients with preeclampsia. A luciferase reporter assay demonstrated that Cox­2 was a potential miR­144­3p target gene and the result was verified by western blotting. A negative correlation was observed between miR­144­3p and Cox­2 in preeclamptic placenta by immunohistochemical staining and in situ hybridization. Western blot analysis demonstrated that overexpression of miR­144­3p decreased Cox­2 expression by 38.2% in HTR­8/SVneo cells. Understanding the differential expression of miR­144­3p and its association with Cox­2 may aid the exploration of the pathogenesis of preeclampsia, and contribute to the development of miRNA­based therapies in the future.


Assuntos
Ciclo-Oxigenase 2/genética , MicroRNAs/genética , Pré-Eclâmpsia/terapia , Adulto , Estudos de Casos e Controles , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Feminino , Regulação da Expressão Gênica , Marcação de Genes , Marcadores Genéticos , Humanos , Hibridização In Situ , MicroRNAs/metabolismo , Placenta , Pré-Eclâmpsia/genética , Gravidez , Adulto Jovem
12.
Mol Med Rep ; 19(6): 5417-5423, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059053

RESUMO

Hepatocellular carcinoma (HCC) has become a global public health problem. Therefore, the development of novel and effective therapeutic agents for the treatment of HCC is considered an emergency. Avicularin, a bio­active flavonoid from plants, has been reported to exhibit diverse pharmacological properties. The aim of the present study was to investigate the role of avicularin in HCC and the underlying mechanism of action. Huh7 cells were treated with avicularin in a concentration­dependent manner, and the cell proliferation was examined using a 3­(4, 5­dimethylthiazol­2­yl)­2, 5­diphenyltetrazolium bromide assay kit. The cell migration and invasion abilities were detected using wounding­healing assays and Transwell assays. Flow cytometric analysis was performed to investigate the cell cycle distribution and cell apoptosis. The activity of nuclear factor (NF)­κB (p65), cyclooxygenase­2 (COX­2) and peroxisome proliferator­activated receptor γ (PPAR­Î³) were measured by reverse transcription­quantitative polymerase chain reaction and western blot analyses, respectively. The results indicated that avicularin treatment markedly decreased cell proliferation concentration­dependently in HCC, and inhibited cell migration and invasion in Huh7 cells. It was also found that the treatment of avicularin markedly inhibited the G0/G1­phase cells and decreased the accumulation of S­phase cells in the cell cycle and induced cell apoptosis. In addition, it was confirmed that the anticancer efficacy of avicularin in HCC was dependent on the regulation of NF­κB (p65), COX­2 and PPAR­Î³ activities. In conclusion, the findings suggested that avicularin serves an antineoplastic role in HCC and may provide a potential therapeutic strategy for the treatment of HCC.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/metabolismo , PPAR gama/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/química , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/genética , PPAR gama/genética
13.
Molecules ; 24(10)2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091823

RESUMO

In relation to anti-inflammatory agents from medicinal plants, we have isolated three compounds from Atractylodes macrocephala; 1, 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2, 5-cyclohexadiene-1, 4-dione; 2, 1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol; 3, 1,3-diacetoxy-tetradeca-6E, 12E-diene-8, 10-diyne. Compounds 1-3 showed concentration-dependent inhibitory effects on production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Western blotting and RT-PCR analyses demonstrated that compounds 1-3 suppressed the protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, compounds 1-3 inhibited transcriptional activity of nuclear factor-κB (NF-κB) and nuclear translocation of NF-κB in LPS-activated RAW 264.7 cells. The most active compound among them, compound 1, could reduce the mRNA levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and suppress the phosphorylation of MAPK including p38, JNK, and ERK1/2. Taken together, these results suggest that compounds 1-3 from A. macrocephala can be therapeutic candidates to treat inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Atractylodes/química , Lipopolissacarídeos/efeitos adversos , Macrófagos/metabolismo , Polímero Poliacetilênico/farmacologia , Quinonas/farmacologia , Animais , Anti-Inflamatórios/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polímero Poliacetilênico/química , Quinonas/química , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
14.
Food Funct ; 10(5): 2839-2846, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31062009

RESUMO

Cell signaling is necessary for the organs to co-ordinate with the whole body and it includes response to external stimuli, inflammation, hormonal secretions and other various metabolic functions. In the present study, we have focused on the inflammatory signals modulated by the reactive oxygen and nitrogen species (RONS). Under homeostatic conditions, these species turn on the COX-1-dependent arachidonic acid (AA) pathway towards the release of anti-inflammatory enzymes. However, the excess release of these ions induces negative effects in the form of inflammation by turning on the COX-2-dependent AA pathway to release pro-inflammatory enzymes. In the present study, we observed the shunting of the COX-2-dependent AA pathway towards the release of anti-inflammatory enzymes with the supplementation of organic dietary selenium in the form of seleniferous maize extracts. We observed that 500 nM selenium concentration in Se-maize extracts downregulated the COX-2 and mPGES-1 expressions by 3.8- and 3.2-fold and upregulated the GPx-1 and H-PGDS expressions by 5.0- and 5.4-fold, respectively. To facilitate more availability of Se from the dietary matrices, Se-maize extracts were incubated with rMETase. It was observed that the enzyme-treated cells increased the downregulation of COX-2 and mPGES-1 expressions by 24.8- and 21.0-fold and the upregulation of GPx-1 and H-PGDS expressions by 13.2- and 16.5-fold, respectively.


Assuntos
Macrófagos/efeitos dos fármacos , Prostaglandinas/metabolismo , Selênio/farmacologia , Zea mays/química , Animais , Ácido Araquidônico/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Macrófagos/metabolismo , Camundongos , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Células RAW 264.7 , Selênio/análise
15.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137528

RESUMO

Atopic dermatitis (AD) is a recurrent allergic skin disease caused by genetic and environmental factors. Patients with AD may experience immune imbalance, increased levels of mast cells, immunoglobulin (Ig) E and pro-inflammatory factors (Cyclooxygenase, COX-2 and inducible NO synthase, iNOS). While spilanthol (SP) has anti-inflammatory and analgesic activities, its effect on AD remains to be explored. To develop a new means of SP, inflammation-related symptoms of AD were alleviated, and 2,4-dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in BALB/c mice. Histopathological analysis was used to examine mast cells and eosinophils infiltration in AD-like skin lesions. The levels of IgE, IgG1 and IgG2a were measured by enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used for analysis of the mitogen-activated protein kinase (MAPK) pathways and COX-2 and iNOS protein expression. Topical SP treatment reduced serum IgE and IgG2a levels and suppressed COX-2 and iNOS expression via blocked mitogen-activated protein kinase (MAPK) pathways in DNCB-induced AD-like lesions. Histopathological examination revealed that SP reduced epidermal thickness and collagen accumulation and inhibited mast cells and eosinophils infiltration into the AD-like lesions skin. These results indicate that SP may protect against AD skin lesions through inhibited MAPK signaling pathways and may diminish the infiltration of inflammatory cells to block allergic inflammation.


Assuntos
Antialérgicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Alcamidas Poli-Insaturadas/uso terapêutico , Animais , Antialérgicos/administração & dosagem , Antialérgicos/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Dinitroclorobenzeno/toxicidade , Feminino , Imunoglobulinas/genética , Imunoglobulinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/farmacologia
16.
Medicine (Baltimore) ; 98(18): e15468, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045826

RESUMO

OBJECTIVE: Previous studies have reported an association between cyclooxygenase-2 (COX-2) polymorphism and gastric cancer (GC) susceptibility, but their results are controversial. This meta-analysis was intended to evaluate the relationship between the COX-2 rs20417 polymorphism and GC susceptibility in different ethnic groups. METHODS: We searched PubMed, EMBASE, Web of Knowledge, and the Chinese Biomedical Database (CBM) for relevant case-control studies published up to October 6, 2018, which reported an association between the COX-2 rs20417 polymorphism and gastric cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of this association. RESULTS: 15 papers detailing case-control studies were included in the analysis, which included a total of 2848 GC cases and 4962 healthy controls. The meta-analysis results indicated that the COX-2 rs20417 polymorphism was associated with increased GC susceptibility under allele (G vs C: OR = 1.67, 95%CI = 1.19-2.35, P = .003), heterozygous (GG vs CG: OR = 1.44, 95%CI = 1.03-2.02, P = .034), dominant (GC+CC vs GG: OR = 1.66, 95%CI = 1.18-2.34, P = .004), homozygous (GG vs CC:OR = 2.20, 95%CI = 1.07-4.54, P = .033), and recessive models (CC vs GG+CG:OR = 2.05, 95%CI = 1.09-3.85, P = .025). An analysis of ethnic subgroups revealed that the COX-2 rs20417 polymorphism was significantly associated with GC susceptibility in Asians under all 5 models (G vs C: OR = 2.22, 95%CI = 1.66-2.96, P < .001; GG vs CC: OR = 4.29, 95%CI = 1.94-9.50, P < .001; GG vs CG: OR = 1.86, 95%CI = 1.34-2.58, P < .001; CC vs GG+CG: OR = 3.73, 95%CI = 1.92-7.24, P < .001; GC+CC vs GG: OR = 2.20, 95%CI = 1.65-2.93, P < .001). Helicobacter pylori positive patients suffered a high risk of GC, compared to H pylori negative patients under the dominant model (OR = 3.09, 95%CI = 1.80-5.32, P < .001). CONCLUSION: This meta-analysis of 15 case-control studies provides strong evidence that the COX-2 rs20417 polymorphism increases the risk of GC susceptibility in general populations, especially in Asians. Helicobacter pylori positive patients and those with the COX-2 rs20417 polymorphism had a higher risk of developing GC.


Assuntos
Ciclo-Oxigenase 2/genética , Predisposição Genética para Doença/genética , Infecções por Helicobacter/genética , Polimorfismo Genético/genética , Neoplasias Gástricas/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Infecções por Helicobacter/microbiologia , Helicobacter pylori , Humanos , Razão de Chances , Neoplasias Gástricas/microbiologia
17.
Cell Physiol Biochem ; 52(6): 1517-1534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120230

RESUMO

BACKGROUND/AIMS: Cadmium (Cd) is a heavy metal contaminant whose toxicity is associated with colorectal cancer (CRC). However, the underlying molecular mechanisms of Cd-induced CRC malignancy remain obscure. METHODS: A monolayer scratch assay was employed to assess the migration of HT-29 human adenocarcinoma cells. Luciferase reporter assay was used to determine cyclooxygenase-2 (COX-2) transcriptional activity, and Western blotting was used to detect p38 Mitogen Activated Protein Kinase (MAPK) and Akt phosphorylation as well as COX-2 expression. Prostaglandin E2 (PGE2) levels were measured using Enzyme Linked Immunosorbent Assay (ELISA) and reactive oxygen species (ROS) formation was assessed using dihydroethidium (DHE) stain. RESULTS: Here, we show that Cd potentiates the migratory capacity of HT-29 CRC cells. Cd caused a time-dependent increase in COX-2 expression. Celecoxib, a COX-2 selective inhibitor, significantly reduced Cd-induced migration. Cd also increased levels of ROS and phosphorylated p38. Importantly, Cd-induced COX-2 expression and migration were significantly abolished by N-Acetyl-Cysteine (NAC), a ROS scavenger, or SB202190, a specific p38 inhibitor. Furthermore, Cd-induced p38 phosphorylation was inhibited by NAC. Cd (100 nM) also increased PGE2 levels, which was abrogated by NAC, SB202190, or celecoxib. Exogenous PGE2 significantly potentiated cell migration. Cd caused a significant increase in Akt phosphorylation in a ROS-mediated pathway. Moreover, Cd-induced migration was significantly attenuated by LY294 002, a phosphatidylinositol-3-kinase inhibitor. CONCLUSION: Taken together, our results suggest that exposure to low levels of Cd promotes a more migratory cancer phenotype in a ROS-p38-COX-2-PGE2 pathway as well as ROS-Akt pathway. Therefore, COX-2, PGE2 receptors or Akt represent potential targets in the treatment of CRC, particularly in patients exposed to Cd.


Assuntos
Adenocarcinoma/induzido quimicamente , Cádmio/toxicidade , Neoplasias do Colo/induzido quimicamente , Ciclo-Oxigenase 2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Ativação Enzimática/efeitos dos fármacos , Células HT29 , Humanos , Ativação Transcricional/efeitos dos fármacos
18.
Anticancer Res ; 39(5): 2307-2315, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092422

RESUMO

BACKGROUND: Several studies have highlighted hyperthermia's ability to enhance the effectiveness of radiation and chemotherapy in various in vitro and in vivo cancer models. MATERIALS AND METHODS: In vivo murine models of malignant melanoma and colon carcinoma were utilized for demonstrating hyperthermia's therapeutic effectiveness by examining levels of caspase 3, COX-2 and phospho-H2A.X (Ser139) as endpoints of apoptosis, proliferation and DNA damage respectively. RESULTS: Hyperthermia induced in vitro cytotoxicity in malignant melanoma (B16-F10) and colon carcinoma (CT26) cell lines. In addition, it reduced post-in vitro proliferation and suppression of tumor growth by inducing the expression of caspase-3 and phospho-H2A.X (Ser139) while reducing the expression of COX-2 in both murine cancer models. CONCLUSION: Hyperthermia can exert therapeutic effectiveness against melanoma and colon carcinoma by inhibiting a number of critical cellular cascades including apoptosis, proliferation and DNA damage.


Assuntos
Neoplasias do Colo/terapia , Hipertermia Induzida , Melanoma Experimental/terapia , Melanoma/terapia , Animais , Apoptose/efeitos da radiação , Carcinoma/patologia , Carcinoma/terapia , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Dano ao DNA/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/genética , Histonas/genética , Humanos , Melanoma/patologia , Melanoma Experimental/genética , Camundongos
19.
Mol Med Rep ; 19(6): 4964-4972, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942419

RESUMO

Salidroside (SDS) is a phenylpropanoid glycoside isolated from Rhodiola rosea L. It exhibits multiple pharmacological properties in clinical medicine and has been commonly used in traditional Chinese medicine. The present study investigated the inhibitory effects of SDS on tumor invasion and migration, and the expression of metastasis­related genes in highly metastatic hepatocellular carcinoma (HCC) cells (MHCC97H) in vitro. The underlying mechanisms of SDS on the tumor metastasis were also explored. SDS was found to significantly reduce wound closure areas and inhibit cell migration. In addition, SDS markedly inhibited the invasion of these cells into Matrigel­coated membranes. SDS markedly downregulated the expression of Notch1, Snail, COX­2, MMP­2, MMP­9 genes and upregulated the expression of E­cadherin in a dose­dependent manner. Furthermore, SDS inhibited the expression of the Notch signaling target genes, Hey1, Hes1 and Hes5. On the whole, the findings of this study suggest that SDS inhibits HCC cell metastasis by modulating the activity of the Notch1 signaling pathway.


Assuntos
Glucosídeos/farmacologia , Fenóis/farmacologia , Receptor Notch1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Caderinas/genética , Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Receptor Notch1/antagonistas & inibidores , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo
20.
Minerva Med ; 110(5): 419-424, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30938133

RESUMO

BACKGROUND: Osteoarthritis (OA) is a common worldwide disease induced by a wide range of biochemical processes, mainly inflammation and degradation of collagen. The aim of this study, was to describe the effect of a multistrain probiotic (PB) and chondroitin sulfate (CS), administered separately or in combination, on the expression of Ptgs2, Tgfb1 and Col2a1 during monoiodoacetate-induced OA in male rats. METHODS: OA was induced in male rats by injecting monoiodoacetate in right hind knee. Therapeutic groups received 3 mg/kg of CS for 28 days and/or 1.4 g/kg of multistrain PB for 14 days. Knee cartilage were taken 30 days after monoiodoacetate injection. RNA was extracted and the expression of Ptgs2, Tgfb1 and Col2a1 were analyzed using SYBR Green 1-step real-time quantitative polymerase chain reaction. RESULTS: Induction of OA caused an upregulation in Ptgs2, Tgfb1 expression, and downregulation of Col2a1. Separate administration of PB and CS reduced Ptgs2 and Tgfb1 expressions. Their combined administration significantly decreased the expression of these pro-inflammatory cytokines, comparable to controls. Expression of Col2a1 showed similar behavior, with upregulation in therapeutic group with separate administration and the cumulative effects in case of co-administration. CONCLUSIONS: The multistrain PB diet may offer a perspective to improve the standard treatment of OA and, necessitates further investigation with clinical trials.


Assuntos
Sulfatos de Condroitina/uso terapêutico , Colágeno Tipo II/biossíntese , Ciclo-Oxigenase 2/biossíntese , Osteoartrite do Joelho/dietoterapia , Osteoartrite do Joelho/tratamento farmacológico , Probióticos/uso terapêutico , Fator de Crescimento Transformador beta1/biossíntese , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Sulfatos de Condroitina/administração & dosagem , Colágeno Tipo II/genética , Ciclo-Oxigenase 2/genética , Avaliação Pré-Clínica de Medicamentos , Interações Alimento-Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Iodoacético/toxicidade , Masculino , Microbiota , Osteoartrite do Joelho/induzido quimicamente , Osteoartrite do Joelho/metabolismo , RNA Mensageiro/biossíntese , Ratos , Fator de Crescimento Transformador beta1/genética
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