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1.
J Appl Oral Sci ; 28: e20190699, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401938

RESUMO

Purpose To evaluate the kinetics of apical periodontitis development in vivo , induced either by contamination of the root canals by microorganisms from the oral cavity or by inoculation of bacterial lipopolysaccharide (LPS) and the regulation of major enzymes and receptors involved in the arachidonic acid metabolism. Methodology Apical periodontitis was induced in C57BL6 mice (n=96), by root canal exposure to oral cavity (n=48 teeth) or inoculation of LPS (10 µL of a suspension of 0.1 µg/µL) from E. coli into the root canals (n= 48 teeth). Healthy teeth were used as control (n=48 teeth). After 7, 14, 21 and 28 days the animals were euthanized and tissues removed for histopathological and qRT-PCR analyses. Histological analysis data were analyzed using two-way ANOVA followed by Sidak's test, and qRT-PCR data using two-way ANOVA followed by Tukey's test (α=0.05). Results Contamination by microorganisms led to the development of apical periodontitis, characterized by the recruitment of inflammatory cells and bone tissue resorption, whereas inoculation of LPS induced inflammatory cells recruitment without bone resorption. Both stimuli induced mRNA expression for cyclooxygenase-2 and 5-lipoxygenase enzymes. Expression of prostaglandin E 2 and leukotriene B 4 cell surface receptors were more stimulated by LPS. Regarding nuclear peroxisome proliferator-activated receptors (PPAR), oral contamination induced the synthesis of mRNA for PPARδ, differently from inoculation of LPS, that induced PPARα and PPARγ expression. Conclusions Contamination of the root canals by microorganisms from oral cavity induced the development of apical periodontitis differently than by inoculation with LPS, characterized by less bone loss than the first model. Regardless of the model used, it was found a local increase in the synthesis of mRNA for the enzymes 5-lipoxygenase and cyclooxygenase-2 of the arachidonic acid metabolism, as well as in the surface and nuclear receptors for the lipid mediators prostaglandin E2 and leukotriene B4.


Assuntos
Cavidade Pulpar/microbiologia , Dinoprostona/metabolismo , Leucotrieno B4/metabolismo , Lipopolissacarídeos/metabolismo , Periodontite Periapical/microbiologia , Animais , Araquidonato 5-Lipoxigenase/análise , Araquidonato 5-Lipoxigenase/metabolismo , Reabsorção Óssea/metabolismo , Reabsorção Óssea/microbiologia , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Cavidade Pulpar/metabolismo , Cavidade Pulpar/patologia , Dinoprostona/análise , Expressão Gênica , Leucotrieno B4/análise , Masculino , Camundongos Endogâmicos C57BL , Periodontite Periapical/metabolismo , Periodontite Periapical/patologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Distribuição Aleatória , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
2.
J Biochem Mol Toxicol ; 33(11): e22400, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31593355

RESUMO

Inflammatory bowel disease (IBD) is a continual ailment condition which engrosses the entire alimentary canal. The IBD can be primarily distinguished into two forms, ulcerative colitis, and Crohn's disease. The major symptoms of IBD include pustules or abscesses, severe abdominal pain, diarrhea, fistula, and stenosis, which may directly affect the patient's quality of life. A variety of mediators can stimulate the circumstances of IBD, some examples include infections by microbes such as bacteria, perturbation of the immune system and the surrounding environment of the intestines. Severe colitis was stimulated in the experimental animals through administering 4% dextran sulfate sodium (DSS) which is mixed in water ad libitum for 6 days. Eriocitrin (30 mg/kg) was then administered to the experimental animals followed by the induction of severe colitis to evaluate the therapeutic prospective of eriocitrin against the colon inflammation stimulated by DSS. In this study, eriocitrin (30 mg/kg) demonstrated significant (P < .05) attenuation activity against the DSS-stimulated severe colitis in experimental animals. Eriocitrin counteracted all of the clinical deleterious effects induced by DSS, such as body-weight loss, colon shortening, histopathological injury, accretion of infiltrated inflammatory cells at the inflamed region and the secretion of inflammatory cytokines. The results clearly showed that eriocitrin effectively attenuated DSS-induced acute colitis in experimental animals.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/farmacologia , Flavanonas/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/administração & dosagem , Citrus/química , Colo/efeitos dos fármacos , Colo/patologia , Ciclo-Oxigenase 2/análise , Citocinas/metabolismo , Modelos Animais de Doenças , Flavanonas/administração & dosagem , Inflamação/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/análise , Peroxidase/metabolismo , Extratos Vegetais/administração & dosagem , Índice de Gravidade de Doença , Perda de Peso/efeitos dos fármacos
3.
J Orthop Res ; 37(12): 2550-2560, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31373395

RESUMO

Osteoarthritis (OA) is a degenerative joint disease associated with chronic pain and disability in humans and companion animals. The canine species can be subdivided into non-chondrodystrophic (NCD) and chondrodystrophic (CD) dogs, the latter having disproportionally short limbs due to disturbance in endochondral ossification of long bones. This phenotype is associated with retrogene insertions of the fibroblast growth factor 4 (FGF4) gene, resulting in enhanced fibroblast growth factor receptor 3 (FGFR3) signaling. The effect on cartilage is unknown and in experimental studies with dogs, breeds are seemingly employed randomly. The aim of this study was to determine whether CD- and NCD-derived cartilage differs on a structural and biochemical level, and to explore the relationship between FGF4 associated chondrodystrophy and OA. Cartilage explants from CD and NCD dogs were cultured for 21 days. Activation of canonical Wnt signaling was assessed in primary canine chondrocytes. OA and synovitis severity from an experimental OA model were compared between healthy and OA samples from CD and NCD dogs. Release of glycosaminoglycans, DNA content, and cyclooxygenase 2 (COX-2) expression were higher in NCD cartilage explants. Healthy cartilage from NCD dogs displayed higher cartilage degeneration and synovitis scores, which was aggravated by the induction of OA. Dikkopf-3 gene expression was higher in NCD cartilage. No differences in other Wnt pathway read outs were found. To conclude, chondrodystrophy associated with the FGF4 retrogene seems to render CD dogs less susceptible to the development of OA when compared with NCD dogs. These differences should be considered when choosing a canine model to study the pathobiology and new treatment strategies of OA. © 2019 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. J Orthop Res 37:2550-2560, 2019.


Assuntos
Modelos Animais de Doenças , Fator 4 de Crescimento de Fibroblastos/genética , Osteoartrite/etiologia , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Animais , Cartilagem Articular/patologia , Ciclo-Oxigenase 2/análise , Cães , Glicosaminoglicanos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/fisiologia , Via de Sinalização Wnt
4.
Med Hypotheses ; 131: 109322, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443756

RESUMO

Bladder cancer is one of the most common urogenital tumors. Its prevalence is increasing worldwide, especially men. The cyclooxygenase-2 (COX-2) enzyme has been shown to increase in bladder cancer and has a direct relationship with tumor progression. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce the growth of the tumor by inhibiting the COX-2 enzyme. NSAIDs have other effects unrelated to COX that provide anticancer properties. Also, similar to NSAIDs, anticancer effects of paracetamol have been shown in many studies. Therefore we hypothesize intravesical paracetamol application will have beneficial effects in the treatment of non-muscle invasive bladder cancer (NMBIC).


Assuntos
Acetaminofen/administração & dosagem , Anti-Inflamatórios não Esteroides/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Modelos Biológicos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Vacina BCG/uso terapêutico , Carcinógenos Ambientais/efeitos adversos , Ciclo-Oxigenase 2/análise , Sinergismo Farmacológico , Humanos , Imunoterapia/métodos , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/antagonistas & inibidores , Fumar/efeitos adversos , Neoplasias da Bexiga Urinária/enzimologia , Neoplasias da Bexiga Urinária/etiologia
5.
J Appl Oral Sci ; 27: e20180641, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31166414

RESUMO

OBJECTIVES: Infection, inflammation and bone resorption are closely related events in apical periodontitis development. Therefore, we sought to investigate the role of cyclooxygenase (COX) in osteoclastogenesis and bone metabolism signaling in periapical bone tissue after bacterial lipopolysaccharide (LPS) inoculation into root canals. METHODOLOGY: Seventy two C57BL/6 mice had the root canals of the first molars inoculated with a solution containing LPS from E. coli (1.0 mg/mL) and received selective (celecoxib) or non-selective (indomethacin) COX-2 inhibitor. After 7, 14, 21 and 28 days the animals were euthanized and the tissues removed for total RNA extraction. Evaluation of gene expression was performed by qRT-PCR. Statistical analysis was performed using analysis of variance (ANOVA) followed by post-tests (α=0.05). RESULTS: LPS induced expression of mRNA for COX-2 (Ptgs2) and PGE2 receptors (Ptger1, Ptger3 and Ptger4), indicating that cyclooxygenase is involved in periapical response to LPS. A signaling that favours bone resorption was observed because Tnfsf11 (RANKL), Vegfa, Ctsk, Mmp9, Cd36, Icam, Vcam1, Nfkb1 and Sox9 were upregulated in response to LPS. Indomethacin and celecoxib differentially modulated expression of osteoclastogenic and other bone metabolism genes: celecoxib downregulated Igf1r, Ctsk, Mmp9, Cd36, Icam1, Nfkb1, Smad3, Sox9, Csf3, Vcam1 and Itga3 whereas indomethacin inhibited Tgfbr1, Igf1r, Ctsk, Mmp9, Sox9, Cd36 and Icam1. CONCLUSIONS: We demonstrated that gene expression for COX-2 and PGE2 receptors was upregulated after LPS inoculation into the root canals. Additionally, early administration of indomethacin and celecoxib (NSAIDs) inhibited osteoclastogenic signaling. The relevance of the cyclooxygenase pathway in apical periodontitis was shown by a wide modulation in the expression of genes involved in both bone catabolism and anabolism.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Cavidade Pulpar/metabolismo , Lipopolissacarídeos/farmacologia , Osteogênese/fisiologia , Tecido Periapical/efeitos dos fármacos , Tecido Periapical/metabolismo , Prostaglandina-Endoperóxido Sintases/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Reabsorção Óssea/metabolismo , Celecoxib/farmacologia , Ciclo-Oxigenase 2/análise , Escherichia coli/metabolismo , Expressão Gênica , Indometacina/farmacologia , Lipopolissacarídeos/análise , Masculino , Camundongos Endogâmicos C57BL , Osteogênese/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/análise , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Receptores de Prostaglandina E/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Regulação para Cima
6.
Int J Dermatol ; 58(12): 1444-1450, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31218676

RESUMO

BACKGROUND: Lichen planus (LP) is an inflammatory disease that affects skin, hair follicles, mucous membranes, and nails. Ki-67 is an antigen associated with the proliferation of cells in all stages of cell cycle except G0. Bcl-2 is a protooncogene that protects cells from apoptosis. COX-2 is an antiapoptotic protein that increases in inflammation. The infiltration of T cells in LP seems to be responsible in the apoptosis of the basal keratinocytes. OBJECTIVE: The purpose of this study was to investigate the effects of prednisolone and acitretin treatments on Ki-67, Bcl-2, and COX-2 expression and apoptosis in patients with LP and the role of Ki-67, Bcl-2, and COX-2 proteins in LP. METHODS: Fifty-eight patients with clinically and histopathologically diagnosed LP who had not been treated with systemic treatment before and 15 healthy volunteers were evaluated prospectively. Pretreatment and posttreatment biopsies were immunohistochemically stained with Ki-67, Bcl-2, and COX-2. The percentage of the stained cells were calculated and recorded. RESULTS: Although the percentage of staining with Ki-67 and Bcl-2 after treatment with prednisolone and acitretin decreased significantly (P < 0.05) in both groups, there was no significant difference between groups (P > 0.05). COX-2 decreased but was not statistically significant. CONCLUSIONS: With this study in cutaneous lichen planus, prednisolone and acitretin treatments reduced Bcl-2 and Ki-67 levels and did not effect COX-2 levels. It should be clarified whether these results can be obtained with any treatment effective in cutaneous lichen planus.


Assuntos
Acitretina/administração & dosagem , Ceratolíticos/administração & dosagem , Líquen Plano/tratamento farmacológico , Prednisolona/administração & dosagem , Pele/patologia , Administração Oral , Adolescente , Adulto , Idoso , Apoptose/efeitos dos fármacos , Biópsia , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Líquen Plano/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pele/efeitos dos fármacos , Adulto Jovem
7.
Int J Mol Sci ; 20(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181746

RESUMO

Exposure to ultrafine particles (UFPs) leads to adverse effects on health caused by an unbalanced ratio between UFPs deposition and clearance efficacy. Since air pollution toxicity is first direct to cardiorespiratory system, we compared the acute and sub-acute effects of diesel exhaust particles (DEP) and biomass burning-derived particles (BB) on bronchoalveolar Lavage Fluid (BALf), lung and heart parenchyma. Markers of cytotoxicity, oxidative stress and inflammation were analysed in male BALB/c mice submitted to single and repeated intra-tracheal instillations of 50 µg UFPs. This in-vivo study showed the activation of inflammatory response (COX-2 and MPO) after exposure to UFPs, both in respiratory and cardiovascular systems. Exposure to DEP results also in pro- and anti-oxidant (HO-1, iNOS, Cyp1b1, Hsp70) protein levels increase, although, stress persist only in cardiac tissue under repeated instillations. Statistical correlations suggest that stress marker variation was probably due to soluble components and/or mediators translocation of from first deposition site. This mechanism, appears more important after repeated instillations, since inflammation and oxidative stress endure only in heart. In summary, chemical composition of UFPs influenced the activation of different responses mediated by their components or pro-inflammatory and pro-oxidative molecules, indicating DEP as the most damaging pollutant in the comparison.


Assuntos
Exposição por Inalação/efeitos adversos , Material Particulado/toxicidade , Emissões de Veículos/toxicidade , Animais , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Ciclo-Oxigenase 2/análise , Citocromo P-450 CYP1B1/análise , Proteínas de Choque Térmico HSP70/análise , Heme Oxigenase-1/análise , Inflamação/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/análise
8.
Sao Paulo Med J ; 137(1): 33-38, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31116268

RESUMO

BACKGROUND: There are cases of colorectal tumors that, although small, show more aggressive evolution than large tumors. This motivated us to study whether there are any proteins capable of alerting about these changes. The aim here was to correlate the immunoexpression of the TS, p53, COX2, EGFR, MSH6 and MLH1 biomarkers in tumors in patients with colorectal adenocarcinoma, with the degree of cell differentiation, tumor staging and clinical-pathological prognostic factors. DESIGN AND SETTING: Retrospective observational study at a public tertiary-level hospital. METHODS: We analyzed tissue-microarray paraffin blocks of tumor tissues that had been resected from 107 patients. We used Fisher's exact test to study associations between tumor differentiation/staging and the immunoexpression of biomarkers. We also used Kaplan-Meier estimation, the log-rank test and the adjusted Cox regression model to investigate the patients' overall survival (in months) according to biomarkers and disease-free interval. RESULTS: The degree of tumor differentiation and tumor staging were not associated with the biomarkers, except in cases of patients in stages III or IV, in which there was a correlation with MLH1 expression (P=0.021). Patient survival and disease-free interval were not associated with the biomarkers. CONCLUSION: There were no associations between the degree of tumor differentiation, staging, length of survival or disease-free interval and the immunoexpression of the TS, p53, COX2, EGFR or MSH6 tumor markers. In advanced cases of colorectal adenocarcinoma (stages III and IV), there was a higher percentage of MLH1-negative results.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/análise , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclo-Oxigenase 2/análise , Proteínas de Ligação a DNA/análise , Receptores ErbB/análise , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/análise , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Valores de Referência , Estudos Retrospectivos , Timidilato Sintase/análise , Análise Serial de Tecidos , Proteína Supressora de Tumor p53/análise , Adulto Jovem
9.
World J Gastroenterol ; 25(4): 433-446, 2019 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-30700940

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. It is broadly described that cyclooxygenase-2 (COX-2) is mainly overexpressed in CRC but less is known regarding post-translational modifications of this enzyme that may regulate its activity, intracellular localization and stability. Since metabolic and proteomic profile analysis is essential for cancer prognosis and diagnosis, our hypothesis is that the analysis of correlations between these specific parameters and COX-2 state in tumors of a high number of CRC patients could be useful for the understanding of the basis of this cancer in humans. AIM: To analyze COX-2 regulation in colorectal cancer and to perform a detailed analysis of their metabolic and proteomic profile. METHODS: Biopsies from both healthy and pathological colorectal tissues were taken under informed consent from patients during standard colonoscopy procedure in the University Hospital of Bellvitge (Barcelona, Spain) and Germans Trias i Pujol University Hospital (Campus Can Ruti) (Barcelona, Spain). Western blot analysis was used to determine COX-2 levels. Deglycosylation assays were performed in both cells and tumor samples incubating each sample with peptide N-glycosidase F (PNGase F). Prostaglandin E2 (PGE2) levels were determined using a specific ELISA. 1H high resolution magic angle spinning (HRMAS) analysis was performed using a Bruker AVIII 500 MHz spectrometer and proteomic analysis was performed in a nano-liquid chromatography-tandem mass spectrometer (nano LC-MS/MS) using a QExactive HF orbitrap MS. RESULTS: Our data show that COX-2 has a differential expression profile in tumor tissue of CRC patients vs the adjacent non-tumor area, which correspond to a glycosylated and less active state of the protein. This fact was associated to a lesser PGE2 production in tumors. These results were corroborated in vitro performing deglycosylation assays in HT29 cell line where COX-2 protein profile was modified after PNGase F incubation, showing higher PGE2 levels. Moreover, HRMAS analysis indicated that tumor tissue has altered metabolic features vs non-tumor counterparts, presenting increased levels of certain metabolites such as taurine and phosphocholine and lower levels of lactate. In proteomic experiments, we detected an enlarged number of proteins in tumors that are mainly implicated in basic biological functions like mitochondrial activity, DNA/RNA processing, vesicular trafficking, metabolism, cytoskeleton and splicing. CONCLUSION: In our colorectal cancer cohort, tumor tissue presents a differential COX-2 expression pattern with lower enzymatic activity that can be related to an altered metabolic and proteomic profile.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Ciclo-Oxigenase 2/metabolismo , Processamento de Proteína Pós-Traducional , Proteoma/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biópsia , Estudos de Coortes , Colo/diagnóstico por imagem , Colo/patologia , Colonoscopia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Ciclo-Oxigenase 2/análise , Dinoprostona/análise , Feminino , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Masculino , Metaboloma , Metabolômica/métodos , Pessoa de Meia-Idade , Proteômica/métodos , Espanha
10.
Biomed Chromatogr ; 33(6): e4500, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30697775

RESUMO

Traditional herbal medicine consists of multiple components. There are interactions among the components, which affect both potency and toxicity. The preparation of herbal medicines can be a cause of interactions between multicomponents in herbs. To demonstrate the differences in multiherb interactions based on the preparation methods, the changes in the active components in the different preparations of Socheongryong-tang (SCRT) were evaluated using metabolomics profiling. We performed multicomponent profiling of the decoction of SCRT (SCRTD) and individual herb mixture (SCRTM) using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Active compounds from SCRTD and SCRTM were identified using multivariate analysis, and the activities between the two groups were compared. We also evaluated the anti-inflammatory effect of SCRT through investigating the protein expression of iNOS and COX-2 in lipopolysaccharide-induced macrophage RAW 264.7 cells in both groups. From the multivariate analysis, 53 active compounds that have different intensities between SCRTD and SCRTM were identified. The intensities of those components, such as ephedrines, glycyrrhizic acid, 6-gingerol and (2E,4E,8Z,10E)-N-isobutyl-2,4,8,10-dodecatetraenamide, which is newly identified in Asiasarum heterotropoides, were mostly higher in SCRTD than in SCRTM, which was related to the anti-inflammatory effect. From the iNOS inhibition test, it was found that SCRTD had a stronger anti-inflammatory effect than SCRTM. It was demonstrated that multicomponent interactions can be changed by the preparation method, and finally the anti-inflammatory effect in SCRT can be affected.


Assuntos
Medicamentos de Ervas Chinesas , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Animais , Anti-Inflamatórios/análise , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Interações Medicamentosas , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Espectrometria de Massas/métodos , Camundongos , Óxido Nítrico Sintase Tipo II/análise , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7
11.
J Agric Food Chem ; 67(7): 1784-1794, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30673264

RESUMO

Commercial malathion is a racemic mixture that contains two enantiomers, and malathion has adverse effects on mammals. However, whether these two enantiomers have different effects on animals remains unclear. In this study, we tested the effect of racemate, enantiomers, and metabolite of malathion on the metabolomics profile of HepG2 cells. HepG2 cells showed distinct metabolic profiles when treated with rac-malathion, malaoxon, R-(+)-malathion, and S-(-)-malathion, and these differences were attributed to pathways in amino acid metabolism, oxidative stress, and inflammatory response. In addition, malathion treatment caused changes in amino acid levels, antioxidant activity, and expression of inflammatory genes in HepG2 cells. S-(-)-Malathion exhibited stronger metabolic perturbation than its enantiomer and racemate, consistent with the high level of cytotoxicity of S-(-)malathion. R-(+)-Malathion treatment caused significant oxidative stress in HepG2 cells but induced a weaker disturbance in the amino acid metabolism and a pro-inflammatory response compared to S-(-)-malathion and rac-malathion. Malaoxon caused more significant perturbation on antioxidase and a stronger antiapoptosis effect than its parent malathion. Our results provide insight into the risk assessment of malathion enantiomers and metabolites. We also demonstrate that a metabolomics approach can identify the discrepancy of the toxic effects and underlying mechanisms for enantiomers and metabolites of chiral pesticides.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Malation/química , Malation/toxicidade , Metabolômica/métodos , Aminoácidos/metabolismo , Antioxidantes/análise , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/genética , Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Inflamação/genética , Malation/análogos & derivados , Malation/metabolismo , Malation/farmacologia , Estresse Oxidativo , Oxirredutases/antagonistas & inibidores , RNA Mensageiro/análise , Estereoisomerismo
12.
Reprod Sci ; 26(6): 713-723, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29996695

RESUMO

Breast regression protein 39 (Brp-39) is a mouse homolog of human Chitinase 3-like 1, which belongs to the 18-glycosyl-hydrolase family and plays a role in inflammatory reaction and tissue remodeling. The aim of this study is to investigate the role of Brp-39 in a mouse model of preterm birth. Pregnant wild-type (WT) or Brp-39(-/-) mice were injected intraperitoneally with lipopolysaccharide (LPS) at embryonic day 15. Pregnancy outcomes were evaluated for 24 hours after LPS injection. Quantitative real-time polymerase chain reaction and immunoblotting were performed to analyze messenger RNA (mRNA) and protein expressions of cytokines and contraction-associated proteins in uterine and/or placental tissue after LPS injection. LPS injection led to preterm birth in both WT and Brp-39(-/-) mice, but the proportion of pubs delivered was reduced in Brp-39(-/-) mice, along with a longer interval from the LPS injection to delivery, compared to WT mice. Inflammatory cell infiltration and mRNA expression of cytokines and Ptgs2 in the uteri and the placentas were not significantly different between WT and Brp-39(-/-) mice. Par-2 mRNA expression in the WT uteri was increased before delivery after LPS injection and decreased after delivery, while there was no significant change in Par-2 expression in the Brp-39(-/-) uteri. Protein expressions of Par-2 and Ptgs2 were lower in the Brp-39(-/-) uteri than in the WT uteri before and after delivery. Attenuated preterm birth in Brp-39(-/-) mice indicates the significance of Brp-39 during murine preterm birth. Altered expression of Par-2 in Brp-39(-/-) uteri suggests its potential role in attenuated preterm birth of Brp-39(-/-) mice.


Assuntos
Proteína 1 Semelhante à Quitinase-3/deficiência , Proteína 1 Semelhante à Quitinase-3/fisiologia , Expressão Gênica , Nascimento Prematuro/etiologia , Receptor PAR-2/genética , Útero/metabolismo , Animais , Ciclo-Oxigenase 2/análise , Citocinas/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placenta/química , Gravidez , Nascimento Prematuro/genética , RNA Mensageiro/análise , Receptor PAR-2/análise , Útero/química
13.
Oncol Res ; 27(2): 147-155, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-28800785

RESUMO

Glioma is the most common malignant tumor of the nervous system. Studies have shown the microRNA-26b (miR-26b)/cyclooxygenase-2 (COX-2) axis in the development and progression in many tumor cells. Our study aims to investigate the effect and mechanism of the miR-26b/COX-2 axis in glioma. Decreased expression of miR-26b with increased levels of COX-2 was found in glioma tissues compared with matched normal tissues. A strong negative correlation was observed between the level of miR-26b and COX-2 in 30 glioma tissues. The miR-26b was then overexpressed by transfecting a miR-26b mimic into U-373 cells. The invasive cell number and wound closing rate were reduced in U-373 cells transfected with miR-26b mimic. In addition, COX-2 siRNA enhanced the effect of miR-26b mimic in suppressing the expression of p-ERK1 and p-JNK. Finally, the in vivo experiment revealed that miR-26b mimic transfection strongly reduced the tumor growth, tumor volume, and expression of matrix metalloproteinase-2 (MMP-2) and MMP-9. Taken together, our research indicated a miR-26b/COX-2/ERK/JNK axis in regulating the motility of glioma in vitro and in vivo, providing a new sight for the treatment of glioma.


Assuntos
Neoplasias Encefálicas/patologia , Ciclo-Oxigenase 2/genética , Glioma/patologia , MicroRNAs/fisiologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclo-Oxigenase 2/análise , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Sistema de Sinalização das MAP Quinases , Camundongos , MicroRNAs/análise , Invasividade Neoplásica
14.
J Tissue Viability ; 27(4): 249-256, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30318397

RESUMO

Burns are injuries caused mainly by thermal trauma, which can progress to unsatisfactory results healing. This study aimed to evaluate the biomaterial (bacterial cellulose membrane) and photobiomodulation, exclusively and associated, in the treatment of third degree burns in rats. Forty male Wistar rats (±280 g) were randomly divided into four groups, with 10 animals each: control group (CG); bacterial cellulose membrane group (MG); laser group (LG) and bacterial cellulose membrane and laser group (MG + L). The burn was caused with a 1 cm2 aluminum plate heated to 150 °C and pressed on the animal's back for 10 s. The treatments were started immediately after induction of injury. For to laser irradiation (660 nm, 100 mW, 25 J/cm2 and energy of 1 J) on five distinct application points were used, on alternate days, a total of five sessions. After ten days of treatment the animals were euthanized for collected samples. One-way ANOVA and Tukey's tests (P < 0.05) were used. Histological analysis revealed differences regarding the healing process phase in each experimental group. MG showed the proliferative phase. The LG demonstrated greater amount of blood vessels and immune expression of VEGF. However, when the treatments were combined, the number of vessels and the immune expression of VEGF factor was lower than LG. Thus, it was concluded that both treatments proposed (biomaterial and LLLT) are good alternatives for third degree burns when applied isolated because they stimulate the healing process by acting on the modulation of the inflammatory phase and promote stimulation of angiogenesis.


Assuntos
Queimaduras/terapia , Celulose/farmacologia , Terapia com Luz de Baixa Intensidade/normas , Cicatrização/efeitos da radiação , Análise de Variância , Animais , Celulose/administração & dosagem , Celulose/uso terapêutico , Ciclo-Oxigenase 2/análise , Modelos Animais de Doenças , Terapia com Luz de Baixa Intensidade/métodos , Masculino , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/análise
15.
Int Immunopharmacol ; 64: 319-325, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30243067

RESUMO

Psoriasis is a usual immune-mediated inflammatory skin disease with undefined pathogenesis. Aromatic-turmerone (ATM) is a mainly constituent of essential oil from Curcuma longa L. It has been shown to exhibit strong anti-oxidant, anti-tumor activities and anti-inflammatory effects. In this study, we investigated the effects of ATM on imiquimod (IMQ)-induced psoriasis-like BALB/c mice and its molecular mechanisms for anti-inflammatory effect. ATM showed inhibition of the transfer of CD8+ T cells in epidermis, and reduced expression of NF-κB and COX-2 as well as phosphorylation of p38 MAPK. It also decreased the level of TNF-α and IL-6, and down-regulates IL-17 IL-22 and IL-23 mRNA synthesis. Notably, we demonstrated that topically applied ATM alleviated skin inflammation in IMQ-induced mice. These results indicate that ATM, a natural active compound exhibits anti-inflammatory activity and is a promising candidate molecule to treat inflammatory skin diseases, such as psoriasis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Imiquimode/toxicidade , Cetonas/uso terapêutico , Psoríase/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Ciclo-Oxigenase 2/análise , Citocinas/análise , Feminino , Cetonas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/análise , Psoríase/imunologia , Sesquiterpenos/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Nutr Cancer ; 70(6): 946-955, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30183370

RESUMO

Epidemiological and experimental observations have shown that nonsteroidal anti-inflammatory drugs especially selective cyclooxygenase-2 (COX-2) inhibitors and probiotics reduce the incidence risk of colon cancer. Therefore, the present study was designed to assess the prophylactic potentials of probiotics (Lactobacillus acidophilus and Lactobacillus rhamnosus GG) in conjunction with celecoxib, a selective cox-2 inhibitor in 1,2 dimethylhydrazine dihydrochloride (DMH)-induced experimental colon carcinogenesis, a well-established, well appreciated and widely used model for colorectal cancer that shares many similarities to human sporadic colorectal cancer with respect to response to some promotional and preventive agents. More specifically, it was observed that L. rhamnosus GG + celecoxib + DMH-treated animals had significantly reduced aberrant crypt foci (ACF) count and the expression of procarcinogenic molecular markers (ß-catenin, NF-κB, and COX-2) in early experimental colon carcinogenesis compared with probiotic-DMH, celecoxib-DMH or DMH-treated animals. This is the first ever such study to demonstrate that probiotic in conjunction with celecoxib can be opted as an alternate prophylactic strategy in highly susceptible individuals to reduce both the incidence and severity of the life style diseases as prevention is better than cure.


Assuntos
Celecoxib/administração & dosagem , Neoplasias do Colo/prevenção & controle , Lactobacillus acidophilus , Lactobacillus rhamnosus , Probióticos/administração & dosagem , 1,2-Dimetilidrazina , Focos de Criptas Aberrantes/prevenção & controle , Animais , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Ciclo-Oxigenase 2/análise , NF-kappa B/análise , Ratos , Ratos Sprague-Dawley , beta Catenina/análise
17.
Int Immunopharmacol ; 64: 280-288, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30219503

RESUMO

The aim of the present study was to assess if the uninterrupted and prolonged administration of nanoparticles containing diethylcarbamazine (NANO-DEC) would cause liver, kidney and heart toxicity and then analyze for the first time its action in model of liver fibrosis. Thus, NANO-DEC was administered in C57BL/6 mice daily for 48 days, and at the end the blood was collected for biochemical analyzes. In the long-term administration assay, the evaluation of serological parameters (CK-MB, creatinine, ALT, AST and urea) allowed the conclusion that NANO-DEC prolonged administration did not cause hepatic, renal and cardiac damage. For fibrosis assays, C57BL/6 mice were divided into six groups: 1) control (Cont); 2) carbon tetrachloride (CCl4); 3) CCl4 + DEC 25 mg/kg; 4) CCl4 + DEC 50 mg/kg; 5) CCl4 + NANO-DEC 5 mg/kg and 6) CCl4 + NANO-DEC 12.5 mg/kg. Carbon tetrachloride induced hepatic fibrosis observed through increased inflammatory (TNF-α, IL-1ß, COX-2, NO and iNOS) and fibrotic markers (TGF-ß and TIMP-1), changes in the hepatic morphology, high presence of collagen fibers and elevated serum levels of AST, ALT and ALP. Treatment with NANO-DEC exhibited a superior anti-inflammatory and anti-fibrotic effects compared to the DEC traditional formulation, restoring liver morphology, reducing the content of collagen fibers and serological parameters, besides decreasing the expression of inflammatory and fibrotic markers. The present formulation of nanoencapsulated DEC is a well tolerated anti-inflammatory and anti-fibrotic drug and therefore could be a potential therapeutic tool for the treatment of chronic liver disorders.


Assuntos
Dietilcarbamazina/administração & dosagem , Cirrose Hepática Experimental/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Tetracloreto de Carbono , Colágeno/análise , Creatinina/sangue , Ciclo-Oxigenase 2/análise , Dietilcarbamazina/farmacologia , Dietilcarbamazina/uso terapêutico , Composição de Medicamentos , Fígado/patologia , Cirrose Hepática Experimental/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas , Óxido Nítrico/biossíntese
18.
Biochem Biophys Res Commun ; 503(4): 3167-3173, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30149914

RESUMO

The investigation into the potential health risks associated with the use of engineered nanoparticles is a major scientific interest in recent years. The present study elucidated the involvement of pro-inflammatory cytokines, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in carboxylated multi-walled carbon nanotubes (MWCNTs)-induced hepatotoxicity. Pubertal rats were exposed to purified MWCNTs at 0, 0.25, 0.50, 0.75 and 1.0 mg/kg for 5 consecutive days. Results indicated that exposure to MWCNTs caused liver damage evidenced by significant elevation in serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma glutamyl transferase (GGT) when compared with control. Moreover, MWCNTs significantly decreased superoxide dismutase (SOD) and glutathione S-transferase (GST) activities as well as glutathione level whereas it significantly increased catalase (CAT) and glutathione peroxidase (GPx) activities in liver of the treated rats. Moreover, the dose-dependent increase in hepatic hydrogen peroxide (H2O2) and lipid peroxidation levels were accompanied by marked increase in micronucleated polychromatic erythrocytes (MNPCE) in the MWCNTs-treated rats. Administration of MWCNTs significantly increased serum concentrations of pro-inflammatory cytokines namely interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in the treated rats. Immunohistochemical analysis showed significantly increased COX-2 and iNOS protein expressions in the liver of MWCNTs-treated rats. In conclusion, carboxylated MWCNTs induces hepatic damage via disruption of antioxidant defense systems, promotion of pro-inflammatory cytokines generation and expression of COX-2 and i-NOS in rats.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Citocinas/imunologia , Fígado/efeitos dos fármacos , Nanotubos de Carbono/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/imunologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Masculino , Nanotubos de Carbono/química , Óxido Nítrico Sintase Tipo II/análise , Óxido Nítrico Sintase Tipo II/imunologia , Ratos Wistar
19.
Bioorg Med Chem Lett ; 28(14): 2432-2435, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29929881

RESUMO

Radiosynthesis and in vivo evaluation of [11C]4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (methoxy analogue of valdecoxib, [11C]MOV), a COX-2 inhibitor, was conducted in rat and baboon. Synthesis of the reference standard MOV (3), and its desmethyl precursor 2 for radiolabeling were performed using 1,2-diphenylethan-1-one as the starting material in five steps with 15% overall yield. Radiosynthesis of [11C]MOV was accomplished in 40 ±â€¯10% yield and >99% radiochemical purity by reacting the precursor 2 in dimethyl formamide (DMF) with [11C]CH3I followed by removal of the dimethoxytrityl (DMT) protective group using trifluroacetic acid. PET studies in anesthetized baboon showed very low uptake and homogeneous distribution of [11C]MOV in brain. The radioligand underwent rapid metabolism in baboon plasma. MicroPET studies in male Sprague Dawley rats revealed [11C]MOV binding in lower thorax. The tracer binding in rats was partially blocked in heart and duodenum by the administration of 1 mg/kg oral dose of COX-2 inhibitor valdecoxib.


Assuntos
Celecoxib/química , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/análise , Ciclo-Oxigenase 2/metabolismo , Isoxazóis/química , Tomografia por Emissão de Pósitrons , Sulfonamidas/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Radioisótopos de Carbono , Celecoxib/síntese química , Celecoxib/farmacocinética , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Masculino , Estrutura Molecular , Papio , Ratos , Ratos Sprague-Dawley , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
20.
Sci Rep ; 8(1): 8831, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29891860

RESUMO

Motility dysfunction is present not only during bowel obstruction (BO), but after obstruction is resolved. Previous studies found that lumen distension associated mechano-transcription of COX-2 and production of PGE2 in gut smooth muscle cells (SMC) account for motility dysfunction during obstruction. We hypothesized that PGE2 may exert autocrine effect in SMC to induce microsomal prostaglandin E synthase-1 (mPGES-1), which contributes to motility dysfunction after obstruction is resolved. Partial colon obstruction was induced in rats with an obstruction band, which was released 7 days later. Rats were further studied in the post-BO state. Circular muscle contractility of the mid colon (previously distended during obstruction) remained suppressed, and colon transit was impaired in the post-BO state. The COX-2, mPGES-1, and PGE2 levels were all increased in the distended bowel during obstruction. However, after obstruction was resolved, COX-2 expression returned to normal, whereas mPGES-1 and PGE2 levels remained increased. Expression of mPGES-1 in colon SMC was inducible by stretch or PGE2. Administration of mPGES-1 inhibitor Cay 10526 either before or after the release of obstruction normalized PGE2 levels and improved motility in the post-BO rats. In conclusion, mPGES-1 plays a critical role in the continuous suppression of motor function in the post-BO state.


Assuntos
Colo/fisiopatologia , Motilidade Gastrointestinal , Obstrução Intestinal/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Prostaglandina-E Sintases/metabolismo , Animais , Ciclo-Oxigenase 2/análise , Dinoprostona/análise , Modelos Animais de Doenças , Trânsito Gastrointestinal , Ratos
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