Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.824
Filtrar
1.
Life Sci ; 259: 118250, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32791152

RESUMO

AIMS: Several microbial toll-like receptor (TLR) ligands, bacterial DNA and bacterial cell wall fragments have been identified in the synovium of rheumatoid arthritis (RA) patients, proving bacterial involvement in the pathogenesis of RA. The current study aimed to verify that low dose polymyxin B could prevent the development of chronic inflammatory arthritis. METHODS: Twelve days post adjuvant injection, Sprague-Dawley rats were treated twice weekly with methotrexate (0.5 mg/kg) or daily with polymyxin B (1 mg/kg) or with combination of both for 1 or 2 weeks. Arthritis progression was assessed by hind paw swelling, serum levels of tumor growth factor-1ß (TGF-1ß), tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (HS-CRP) and nuclear factor kappa B (NF-κB) were measured using ELISA. Cyclooxygenase-1 (Cox-1) and Cox-2 activities, as well as mRNA expression of TLR-2 and TLR-4 were determined. Histopathological examination of the ankle joint was performed as well as immunohistochemistry for anti-TLR-4. Histopathological assessment of toxic effects on the kidney was performed. KEY FINDINGS: Adjuvant arthritis led to a significant swelling of the hind paw and alteration in all serum parameters, TLR-2 and TLR-4 expression, as well as Cox-2 activity. These alterations were associated with histopathological changes of the joints. Polymyxin B reduced significantly all biomarkers of inflammation, showing better effect of the combination in most of the studied parameters, with minimal signs of nephrotoxicity. SIGNIFICANCE: In conclusion, results showed that polymyxin B possesses significant anti-arthritic activity which may be attributed to inhibition of the TLR-4, NF-κB and Cox-2 signaling pathway.


Assuntos
Artrite Experimental/tratamento farmacológico , Polimixina B/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/fisiopatologia , Artrite Reumatoide/tratamento farmacológico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/fisiologia , Adjuvante de Freund/farmacologia , Inflamação/tratamento farmacológico , Masculino , NF-kappa B/metabolismo , Polimixina B/metabolismo , Polimixina B/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/metabolismo , Receptores Toll-Like/metabolismo , Receptores Toll-Like/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
2.
Int J Nanomedicine ; 15: 5345-5360, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801693

RESUMO

Background: Soft corals have been endorsed as a plentiful source of bioactive compounds with promising anti-inflammatory activities; therefore, exploring their potential as source of anti-inflammatory metabolites has stimulated a growing research interest. Purpose: To investigate the anti-inflammatory potential of the soft coral, Nephthea sp., in its bulk and silver nanostructure. Metabolomics analysis of Nephthea sp., followed by molecular docking studies, was also conducted in order to explore and predict the secondary metabolites that might provide its inhibitory actions on inflammation. Materials and Methods: The petroleum ether and ethyl acetate fractions were used to synthesize silver nanoparticles. The prepared silver nanoparticles were characterized through UV-vis spectrophotometric, transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) analyses. Testing for the anti-inflammatory activity was performed against COX-1 and COX-2. Furthermore, liquid chromatography-mass spectrometry (LC-MS) based metabolomics analysis and molecular docking were also applied. Results: A variety of secondary metabolites were identified, among them, sesquiterpenes were found to prevail. The petroleum ether and acetone fractions of Nephthea sp. showed the highest COX-2 inhibitory activities, possibly attributable to their substantial contents of terpenoids. Additionally, the green synthesized silver nanoparticles of both the petroleum ether and ethyl acetate fractions of Nephthea sp. demonstrated higher anti-COX-2 properties. Conclusion: The obtained results showed the effectiveness of non-targeted metabolomics technique in metabolic profiling of Nephthea sp., helping the search for new bioactive metabolites in future chemical studies on this soft coral. The interesting anti-inflammatory potential of the tested extracts and their nanoparticles could also be relevant to the development of new, effective anti-inflammatory agents.


Assuntos
Antozoários/metabolismo , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Nanopartículas Metálicas/química , Prata/química , Alcanos/química , Animais , Antozoários/química , Anti-Inflamatórios/síntese química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/química , Inibidores de Ciclo-Oxigenase/farmacologia , Química Verde , Humanos , Metabolômica , Simulação de Acoplamento Molecular , Metabolismo Secundário , Sesquiterpenos/análise , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de Fourier
3.
Sci Rep ; 10(1): 10187, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576928

RESUMO

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is known as an ideal target for next generation of anti-inflammatory drugs without the side effects of currently available anti-inflammatory drugs. However, there has been no clinically promising mPGES-1 inhibitor identified through traditional drug discovery and development route. Here we report a new approach, called DREAM-in-CDM (Drug Repurposing Effort Applying Integrated Modeling-in vitro/vivo-Clinical Data Mining), to identify an FDA-approved drug suitable for use as an effective analgesic targeting mPGES-1. The DREAM-in-CDM approach consists of three steps: computational screening of FDA-approved drugs; in vitro and/or in vivo assays; and clinical data mining. By using the DREAM-in-CDM approach, lapatinib has been identified as a promising mPGES-1 inhibitor which may have significant anti-inflammatory effects to relieve various forms of pain and possibly treat various inflammation conditions involved in other inflammation-related diseases such as the lung inflammation caused by the newly identified COVID-19. We anticipate that the DREAM-in-CDM approach will be used to repurpose FDA-approved drugs for various new therapeutic indications associated with new targets.


Assuntos
Anti-Inflamatórios/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Lapatinib/farmacologia , Pneumonia Viral/tratamento farmacológico , Prostaglandina-E Sintases/antagonistas & inibidores , Betacoronavirus , Química Computacional/métodos , Infecções por Coronavirus/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Inflamação/tratamento farmacológico , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/patologia , Prostaglandina-E Sintases/metabolismo
4.
Mutat Res ; 853: 503173, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32522345

RESUMO

The aryl hydrocarbon receptor (AhR) transcription factor is activated by polycyclic aromatic hydrocarbons (PAH) and other ligands. Activated AhR binds to dioxin responsive elements (DRE) and initiates transcription of target genes, including the gene encoding prostaglandin endoperoxide synthase 2 (PTGS-2), which is also activated by the transcription factor NF-ĸB. PTGS-2 catalyzes the conversion of arachidonic acid (AA) into prostaglandins, thromboxanes or isoprostanes. 15-F2t-Isoprostane (IsoP), regarded as a universal marker of lipid peroxidation, is also induced by PAH exposure. We investigated the processes associated with lipid peroxidation in human alveolar basal epithelial cells (A549) exposed for 4 h or 24 h to model PAH (benzo[a]pyrene, BaP; 3-nitrobenzanthrone, 3-NBA) and organic extracts from ambient air particulate matter (EOM), collected in two seasons in a polluted locality. Both EOM induced the expression of CYP1A1 and CYP1B1; 24 h treatment significantly reduced PTGS-2 expression. IsoP levels decreased after both exposure periods, while the concentration of AA was not affected. The effects induced by BaP were similar to EOM except for increased IsoP levels after 4 h exposure and elevated AA concentration after 24 h treatment. In contrast, 3-NBA treatment did not induce CYP expression, had a weak effect on PTGS-2 expression, and, similar to BaP, induced IsoP levels after 4 h exposure and AA levels after 24 h treatment. All tested compounds induced the activity of NF-ĸB after the longer exposure period. In summary, our data suggest that EOM, and partly BaP, reduce lipid peroxidation by a mechanism that involves AhR-dependent inhibition of PTGS-2 expression. The effect of 3-NBA on IsoP levels is probably mediated by a different mechanism independent of AhR activation.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Mutagênicos/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Células A549 , Benzo(a)Antracenos/toxicidade , Benzo(a)pireno/toxicidade , Linhagem Celular Tumoral , Ciclo-Oxigenase 1/metabolismo , Citocromo P-450 CYP1A1/metabolismo , Humanos , NF-kappa B/metabolismo , Material Particulado/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade
5.
Aquat Toxicol ; 223: 105476, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32315829

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used pharmaceuticals to treat pain, fever and inflammation. NSAIDs are also known to have many side effects including adverse effects on reproduction in both humans and animals. As NSAIDs usage is not regulated they are frequently detected at high concentrations in the environment. In order to understand the effect of NSAIDs on zebrafish sex differentiation, we used seven different NSAIDs which were either Cox-1 selective, Cox-1 biased, non-selective or COX-2 selective. We show that at higher concentration, NSAIDs are toxic to zebrafish embryo as they lead to mortality and hatching delay. Gene expression analysis following short term exposure of NSAIDs led to downregulation of female specific genes including zp2, vtg2 foxl2 and wnt4. Long term exposure of larvae to environmentally relevant concentrations of Cox-2 selective and non-selective NSAIDs resulted in male-biased sex ratio which confirmed the qRT-PCR analysis. However, the Cox-1 selective acetylsalicylic acid and the Cox-1 biased ketoprofen did not alter sex ratio. The observed male-biased sex ratio could also be due to induction of apoptosis process as the genes including p21 and casp8 were significantly upregulated following exposure to the Cox-2 selective and the non-selective NSAIDs. The present study indicates that NSAIDs alter sex differentiation in zebrafish, primarily through inhibition of Cox-2. This study clearly demonstrates that the use of NSAIDs and their release into the aquatic environment should be carefully monitored to avoid adverse effects to the aquatic organisms.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Animais , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Desenvolvimento Embrionário/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Humanos , Inflamação , Masculino , Diferenciação Sexual/genética , Peixe-Zebra/genética
6.
J Enzyme Inhib Med Chem ; 35(1): 815-823, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32200655

RESUMO

Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)-2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.


Assuntos
Amidas/farmacologia , Amidoidrolases/antagonistas & inibidores , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/farmacologia , Ibuprofeno/farmacologia , Amidas/síntese química , Amidas/química , Amidoidrolases/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Ibuprofeno/síntese química , Ibuprofeno/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade
7.
Artigo em Inglês | MEDLINE | ID: mdl-32062416

RESUMO

Our objective was to determine whether consumption of a single meal has the potential to alter brain oxylipin content. We examined the cerebrum of mice fed a single high-fat/high-sucrose Western meal or a low-fat/low-sucrose control meal, as well as fasted mice. We found no changes in fatty acid composition of cerebrum across the groups. The cerebral oxylipin profile of mice fed a Western meal is distinct from the profile of mice fed a low-fat/low-sucrose meal. Cerebral gene expression of cyclooxygenase 1, cyclooxygenase 2, and epoxide hydrolase 1 were elevated in Western meal-fed mice compared to low-fat/low-sucrose meal-fed mice. Mice that consumed either meal had lower gene expression of cytochrome P450, family 2, subfamily j, polypeptide 12 than fasted mice. Our data in this hypothesis-generating study indicates that the composition of a single meal has the potential to alter brain oxylipins and the gene expression of the enzymes responsible for their production.


Assuntos
Cérebro/química , Dieta Ocidental/efeitos adversos , Oxilipinas/química , Animais , Cérebro/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Epóxido Hidrolases/metabolismo , Jejum , Regulação da Expressão Gênica , Masculino , Refeições , Proteínas de Membrana/metabolismo , Camundongos
8.
J Enzyme Inhib Med Chem ; 35(1): 610-621, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32013633

RESUMO

Cyclic imides containing 3-benzenesulfonamide, oxime, and ß-phenylalanine derivatives were synthesised and evaluated to elucidate their in vivo anti-inflammatory and ulcerogenic activity and in vitro cytotoxic effects. Most active anti-inflammatory agents were subjected to in vitro COX-1/2 inhibition assay. 3-Benzenesulfonamides (2-4, and 9), oximes (11-13), and ß-phenylalanine derivative (18) showed potential anti-inflammatory activities with 71.2-82.9% oedema inhibition relative to celecoxib and diclofenac (85.6 and 83.4%, respectively). Most active cyclic imides 4, 9, 12, 13, and 18 possessed ED50 of 35.4-45.3 mg kg-1 relative to that of celecoxib (34.1 mg kg-1). For the cytotoxic evaluation, the selected derivatives 2-6 and 8 exhibited weak positive cytotoxic effects (PCE = 2/59-5/59) at 10 µM compared to the standard drug, imatinib (PCE = 20/59). Cyclic imides bearing 3-benzenesulfonamide (2-5, and 9), acetophenone oxime (11-14, 18, and 19) exhibited high selectivity against COX-2 with SI > 55.6-333.3 relative to that for celecoxib [SI > 387.6]. ß-Phenylalanine derivatives 21-24 and 28 were non-selective towards COX-1/2 isozymes as indicated by their SI of 0.46-0.68.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Imidas/farmacologia , Oximas/farmacologia , Fenilalanina/farmacologia , Sulfonamidas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Edema/tratamento farmacológico , Humanos , Imidas/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Oximas/química , Fenilalanina/química , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química
9.
Arch Pharm (Weinheim) ; 353(3): e1900295, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31944384

RESUMO

Some novel derivatives of 2-alkyl 6-substituted pyridazin-3(2H)-ones were synthesized by condensation of 3,6-dichloropyridazine with the sodium salt of benzyl cyanide, followed by hydrolysis and coupling with alkyl halides. The synthesized compounds were screened as cyclooxygenase (COX)-1/COX-2 inhibitors and as analgesic and anti-inflammatory agents. Among the synthesized compounds, 6-benzyl-2-methylpyridazin-3(2H)-one (4a), 6-benzoyl-2-propylpyridazin-3(2H)-one (8b), and 6-(hydroxy(phenyl)methyl)-2-methylpyridazin-3(2H)-one (9a) displayed the highest COX-2 selectivity indices of 96, 99, and 98, respectively, and analgesic efficacies of 47%, 46%, and 45% protection, respectively. Also, compounds 4a, 8b, and 9a showed anti-inflammatory activities of 65%, 60%, and 62% inhibition of edema, respectively, at a dose of 10 mg/kg, which is higher than that of diclofenac (58% inhibition of edema).


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Edema/tratamento farmacológico , Piridazinas/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Ratos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
10.
Int J Mol Sci ; 21(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979417

RESUMO

Chrysin exhibits anti-inflammatory and antioxidant activities. Here, the gastroprotective effect of chrysin was investigated in mouse models of gastric ulcer induced by absolute ethanol, acetic acid, and ischemia-reperfusion injury. The gastric-healing effect was evaluated at 7 and 14 days after treatment; the mechanism of action was verified using the expression of metalloproteinase 2 (MMP-2) and 9 (MMP-9), caspase-3, cyclooxygenase 1 (COX-1) and 2 (COX-2), epidermal growth factor (EGF), and interleukin-10. Chrysin (10 mg/kg) inhibited macroscopic lesions and increased catalase activity in the mouse model established using absolute ethanol. It ameliorated the gastric ulcer caused by acetic acid by improving the expression of inflammatory genes such as COX-2, inhibiting negative remodeling promoted by MMP-9, increasing cell proliferation effect via EGF, and reducing cellular apoptosis by modulating caspase-3. A faster healing effect was evident in the first 7 days of treatment compared to 14 days of treatment, indicating the pharmacological potential of chrysin. Overall, these results demonstrate the potent effect of chrysin in the gastrointestinal tract and elucidate the genes involved in the healing of gastric ulcers. Moreover, an increase in the levels of gastric mucosa defensive factors is involved in the activity of chrysin in the gastric mucosa.


Assuntos
Antiulcerosos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Flavonoides/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Úlcera Gástrica/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Ácido Acético/toxicidade , Animais , Antiulcerosos/farmacologia , Apoptose/genética , Caspase 3/metabolismo , Catalase/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Etanol/toxicidade , Flavonoides/farmacocinética , Flavonoides/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Inflamação , Interleucina-10/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Oxirredução/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/enzimologia
11.
Gastroenterology ; 158(4): 971-984.e10, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31734182

RESUMO

BACKGROUND & AIMS: Prostaglandin E2 (PGE2) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE2 on colorectal cancer (CRC) development. METHODS: We incubated LS174T colorectal cancer cells with PGE2 or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative polymerase chain reaction, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NOD-scidIL-2Rg-/- mice were given injections of LS174T cells, and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes. RESULTS: We identified miRNA 675-5p (miR675-5p) as the miRNA most highly up-regulated by incubation of colorectal cancer cells with PGE2. PGE2 increased expression of miR675-5p by activating expression of Myc, via activation of protein kinase B, also known as (AKT), nuclear factor κB, and ß-catenin. PGE2 increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE2 formed more liver and lung metastases in mice than control LS174T cells. We identified a 3' untranslated region in the TP53 messenger RNA that bound miR675-5p; binding resulted in loss of the p53 protein. Expression of miR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC. CONCLUSIONS: We found that treatment of mice with PGE2 increased CRC cells invasive activity and ability to form liver and lung metastases. PGE2 down-regulates expression of p53 by increasing expression of miR675-5p, which binds to and prevents translation of TP53 messenger RNA. These findings provide insight into the mechanisms by which PGE2 promotes tumor development and progression. Strategies to target PGE2 might be developed for treatment of CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Dinoprostona/genética , MicroRNAs/metabolismo , Metástase Neoplásica/genética , Proteína Supressora de Tumor p53/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Humanos , RNA Longo não Codificante/metabolismo , Células Tumorais Cultivadas , Regulação para Cima/genética
12.
J Biol Chem ; 295(5): 1369-1384, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31871049

RESUMO

Angiotensin-converting enzyme (ACE) affects blood pressure. In addition, ACE overexpression in myeloid cells increases their immune function. Using MS and chemical analysis, we identified marked changes of intermediate metabolites in ACE-overexpressing macrophages and neutrophils, with increased cellular ATP (1.7-3.0-fold) and Krebs cycle intermediates, including citrate, isocitrate, succinate, and malate (1.4-3.9-fold). Increased ATP is due to ACE C-domain catalytic activity; it is reversed by an ACE inhibitor but not by an angiotensin II AT1 receptor antagonist. In contrast, macrophages from ACE knockout (null) mice averaged only 28% of the ATP levels found in WT mice. ACE overexpression does not change cell or mitochondrial size or number. However, expression levels of the electron transport chain proteins NDUFB8 (complex I), ATP5A, and ATP5ß (complex V) are significantly increased in macrophages and neutrophils, and COX1 and COX2 (complex IV) are increased in macrophages overexpressing ACE. Macrophages overexpressing ACE have increased mitochondrial membrane potential (24% higher), ATP production rates (29% higher), and maximal respiratory rates (37% higher) compared with WT cells. Increased cellular ATP underpins increased myeloid cell superoxide production and phagocytosis associated with increased ACE expression. Myeloid cells overexpressing ACE indicate the existence of a novel pathway in which myeloid cell function can be enhanced, with a key feature being increased cellular ATP.


Assuntos
Trifosfato de Adenosina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Células Mieloides/metabolismo , Peptidil Dipeptidase A/metabolismo , Animais , Ciclo do Ácido Cítrico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Neutrófilos/metabolismo , Oxirredução , Estresse Oxidativo , Peptidil Dipeptidase A/genética , Regulação para Cima
13.
Eur J Med Chem ; 185: 111780, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655429

RESUMO

Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC50 = 0.10-22.96 µM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1-258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13-44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of COX-2. The study of SAR revealed favorable cytotoxic outcomes of the aliphatic side chain and 4-thiazolidinone moiety at C6 of the pyrrolizine nucleus, while anti-inflammatory activities was improved with the (hetero)aromatic substituents. The IC50 values which inhibit COX-2 were higher than those needed to inhibit the growth of cancer cell lines. Mechanistic studies also revealed inhibition of multiple kinases by compounds 12, 19 and 22. Moreover, compounds 12, 14, 16 and 22 induced cell cycle arrest and apoptosis in MCF-7 cells. Docking studies revealed nice fitting of the new compounds into COX-1/2. Additionally, compounds 12, 19 and 22 also exhibited higher affinity for CDK2 than CAN508. To sum up, the above-mentioned data highlight these compounds as promising anti-inflammatory and anticancer agents.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Edema/tratamento farmacológico , Pirrolidinas/farmacologia , Tiazolidinas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HT29 , Humanos , Células MCF-7 , Masculino , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Tiazolidinas/química
14.
Int J Mol Sci ; 21(1)2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31878290

RESUMO

Platelets and platelet microparticles (PMPs) play a key role in the pathophysiology of vascular disorders such as coronary artery disease and stroke. In atherosclerosis, for example, the disruption of the plaque exposes endogenous agonists such as collagen, which activates platelets. Platelet hyper-activation and the high levels of PMPs generated in such situations pose a thrombotic risk that can lead to strokes or myocardial infarctions. Interestingly, dietary polyphenols are gaining much attention due to their potential to mimic the antiplatelet activity of treatment drugs such as aspirin and clopidogrel that target the glycoprotein VI (GPVI)-collagen and cyclooxygenease-1 (COX-1)-thromboxane platelet activation pathways respectively. Platelet function tests such as aggregometry and flow cytometry used to monitor the efficacy of antiplatelet drugs can also be used to assess the antiplatelet potential of dietary polyphenols. Despite the low bioavailability of polyphenols, several in vitro and dietary intervention studies have reported antiplatelet effects of polyphenols. This review presents a summary of platelet function in terms of aggregation, secretion, activation marker expression, and PMP release. Furthermore, the review will critically evaluate studies demonstrating the impact of polyphenols on aggregation and PMP release.


Assuntos
Plaquetas/metabolismo , Polifenóis/metabolismo , Aterosclerose/metabolismo , Ciclo-Oxigenase 1/metabolismo , Citometria de Fluxo , Humanos , Testes de Função Plaquetária
15.
EBioMedicine ; 49: 145-156, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31707149

RESUMO

BACKGROUND: Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. METHODS: Patient biopsy samples were evaluated for COX1/2, and thromboxane A2 synthase (TBXAS) expression. Circulating prostaglandins biosynthesis was determined using enzyme immunoassay kits. Anchorage-independent cell growth assay, crystal violet staining assay, and xenograft experiments were conducted to assess BE and EAC cell growth. A surgical mouse model of reflux (i.e., esophagoduodenostomy) was established and samples were analyzed using an enzyme immunoassay kit, immunohistochemistry, immunoblotting, or RT-PCR. Esophageal biopsy samples (pre- and post-intervention) were obtained from a randomized clinical trial in which participants were administered esomeprazole (40 mg) twice daily in combination with an acetylsalicylic acid (ASA) placebo or 81 or 325 mg ASA for 28 days. Esophageal biopsy specimens before and after the intervention period were analyzed. FINDINGS: COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels. ASA suppressed BE and EAC growth by targeting the TXA2 pathway. Additionally, biopsies from 49 patients (with similar baseline characteristics) showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation. INTERPRETATION: This study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. FUNDING: Hormel Foundation, Exact Sciences, Pentax Medical, Intromedic and National Cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Esôfago de Barrett/tratamento farmacológico , Carcinogênese/patologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Neoplasias Esofágicas/tratamento farmacológico , Terapia de Alvo Molecular , Transdução de Sinais , Tromboxano A2/metabolismo , Adenocarcinoma/sangue , Animais , Aspirina/farmacologia , Esôfago de Barrett/sangue , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Neoplasias Esofágicas/sangue , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fator de Transcrição STAT3/metabolismo , Tromboxano A2/sangue
16.
Nutrients ; 11(11)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694290

RESUMO

BACKGROUND: Own mother's milk (OMM) is the optimal nutrition for preterm infants. However, pasteurized donor human milk (DHM) is a valid alternative. We explored the differences of the transcriptome in exfoliated epithelial intestinal cells (EEIC) of preterm infants receiving full feed with OMM or DHM. METHODS: The prospective observational study included preterm infants ≤ 32 weeks' gestation and/or ≤1500 g birthweight. Total RNA from EEIC were processed for genome-wide expression analysis. RESULTS: Principal component analysis and unsupervised hierarchical clustering analysis revealed two clustered groups corresponding to the OMM and DHM groups that showed differences in the gene expression profile in 1629 transcripts. The OMM group overexpressed lactalbumin alpha gene (LALBA), Cytochrome C oxidase subunit I gene (COX1) and caseins kappa gene (CSN3), beta gene (CSN2) and alpha gene (CSN1S1) and underexpressed Neutrophil Cytosolic Factor 1 gene (NCF1) compared to the DHM group. CONCLUSIONS: The transcriptomic analysis of EEIC showed that OMM induced a differential expression of specific genes that may contribute to a more efficient response to a pro-oxidant challenge early in the postnatal period when preterm infants are at a higher risk of oxidative stress. The use of OMM should be strongly promoted in preterm infants.


Assuntos
Células Epiteliais/metabolismo , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Leite Humano/metabolismo , Transcriptoma/genética , Caseínas/metabolismo , Ciclo-Oxigenase 1/metabolismo , Feminino , Expressão Gênica , Idade Gestacional , Humanos , Recém-Nascido , Mucosa Intestinal/citologia , Lactalbumina/metabolismo , Masculino , Bancos de Leite , NADPH Oxidases/metabolismo , Estresse Oxidativo/genética , Análise de Componente Principal , Estudos Prospectivos
17.
Molecules ; 24(22)2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739473

RESUMO

Guettarda speciosa is known in traditional folk medicine for treating cough, cold, sore throat, fever, wounds, epilepsy, and headaches. To discover the scientific pharmacological potential of G. speciosa, we explore its anti-inflammatory, cytotoxicity, and inhibition of amyloid-beta (Aß) aggregation effects. Cyclooxygenase assay of the G. speciosa CHCl3 (GSC) extract and G. speciosa MeOH (GSM) extract are more selective to COX-1 inhibition with a 50% inhibitory concentration (IC50) of 3.56 µg/mL for the GSC extract and 4.98 µg/mL for the GSM extract. Neuroblastoma SH-SY5Y inhibition and thioflavin T assay amyloid-beta (Aß) aggregate inhibition of the GSM and GSC extracts showed their potential therapeutic effects against Alzheimer's disease. The putative compounds from the LC-MS analysis could be responsible for the observed activities. The results suggest that G. speciosa possesses anti-inflammatory and anti-neurodegenerative properties and a promising lead as a source of pharmacologically active compounds.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Ciclo-Oxigenase 1/metabolismo , Extratos Vegetais/uso terapêutico , Rubiaceae/química , Peptídeos beta-Amiloides/metabolismo , Anti-Inflamatórios/uso terapêutico , Benzotiazóis/metabolismo
18.
Molecules ; 24(22)2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31698831

RESUMO

Prostaglandins and inhibitors of their synthesis (cyclooxygenase (COX) inhibitors, non-steroidal anti-inflammatory drugs) were shown to play a significant role in the regulation of hematopoiesis. Partly due to their hematopoiesis-modulating effects, both prostaglandins and COX inhibitors were reported to act positively in radiation-exposed mammalian organisms at various pre- and post-irradiation therapeutical settings. Experimental efforts were targeted at finding pharmacological procedures leading to optimization of therapeutical outcomes by minimizing undesirable side effects of the treatments. Progress in these efforts was obtained after discovery of selective inhibitors of inducible selective cyclooxygenase-2 (COX-2) inhibitors. Recent studies have been able to suggest the possibility to find combined therapeutical approaches utilizing joint administration of prostaglandins and inhibitors of their synthesis at optimized timing and dosing of the drugs which could be incorporated into the therapy of patients with acute radiation syndrome.


Assuntos
Síndrome Aguda da Radiação/metabolismo , Hematopoese/efeitos dos fármacos , Prostaglandinas/biossíntese , Prostaglandinas/farmacologia , Protetores contra Radiação/farmacologia , Síndrome Aguda da Radiação/sangue , Síndrome Aguda da Radiação/tratamento farmacológico , Síndrome Aguda da Radiação/etiologia , Animais , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Modelos Animais de Doenças , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Protetores contra Radiação/uso terapêutico
19.
Life Sci ; 239: 117039, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31704447

RESUMO

AIMS: Obesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity. MAIN METHODS: Small arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n = 65, BMI 45 ±â€¯6 kg m-2 [Mean ±â€¯SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 µM, cyclooxygenase inhibitor), FR122047 (1 µM, cyclooxygenase-1 inhibitor), Celecoxib (4 µM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-NAME, 100 µM, nitric oxide synthase inhibitor) or combination of apamin (0.5 µM) and charybdotoxin (0.1 µM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A2 mimetic) were also studied. KEY FINDINGS: Acetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p < 0.01). Indomethacin (p < 0.01) and FR122047 (p < 0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p < 0.05). L-NAME comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries. SIGNIFICANCE: The results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Artéria Gastroepiploica/efeitos dos fármacos , Receptores de Tromboxanos/metabolismo , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/metabolismo , Adulto , Apamina/farmacologia , Artérias/efeitos dos fármacos , Celecoxib/farmacologia , Charibdotoxina/farmacologia , Ciclo-Oxigenase 1/fisiologia , Inibidores de Ciclo-Oxigenase/farmacologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Artéria Gastroepiploica/metabolismo , Humanos , Indometacina/farmacologia , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Obesidade Mórbida/metabolismo , Omento/irrigação sanguínea , Omento/metabolismo , Receptores de Tromboxanos/fisiologia , Vasodilatação/efeitos dos fármacos
20.
Dalton Trans ; 48(42): 15856-15868, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31617517

RESUMO

The cobalt alkyne complex [(prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) is an auspicious lead, which exhibits its anticancer activity mainly by inhibition of both cyclooxygenases (COX-1 and COX-2). Since COX-2 participates in carcinogenesis, a selective inhibition of that isoenzyme is aimed. To study if fluorination increases the COX-2/COX-1 inhibition ratio of the lead, substitution was respectively performed in the positions 3, 4, 5, and 6 of the aromatic moiety. The complexes 3/4/5F-Co-ASS and to a much lower extent also 6F-Co-ASS showed cytotoxic, antimetabolic, and apoptotic effects in COX-1/2-positive HT-29 and MDA-MB-231 cells and remarkably less activity in the COX-1/2-negative MCF-7 cell line. The metabolic activity in MCF-7 cells was even unaffected up to a concentration of 40 µM. With exception of 6F-Co-ASS, the complexes strongly reduced the PGE2 synthesis in HT-29 cells and all complexes inhibited COX-2 more effectively than COX-1 in an assay at isolated enzymes. These findings point to an interference in the COX cascade as part of the mode of antitumor action. The limited cellular effects of 6F-Co-ASS are related to its poor uptake as determined by HR CS AAS/MAS. Moreover, the cellular uptake studies confirm fluorination as beneficial tool for bioanalytical labeling. The higher quantification of fluorine by HR CS MAS makes this method about 5-fold more sensitive than HR CS AAS measuring cobalt. As a further positive result, 3/4/5/6-Co-ASS demonstrated high selectivity to tumor cells due to lack of antimetabolic activity against the non-tumorigenic bone marrow stromal cell line HS-5.


Assuntos
Alquinos/química , Antineoplásicos/química , Cobalto/química , Complexos de Coordenação/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/metabolismo , Halogenação , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA