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1.
NPJ Syst Biol Appl ; 5: 23, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341635

RESUMO

A biological reaction network may serve multiple purposes, processing more than one input and impacting downstream processes via more than one output. These networks operate in a dynamic cellular environment in which the levels of network components may change within cells and across cells. Recent evidence suggests that protein concentration variability could explain cell fate decisions. However, systems with multiple inputs, multiple outputs, and changing input concentrations have not been studied in detail due to their complexity. Here, we take a systems biochemistry approach, combining physiochemical modeling and information theory, to investigate how cyclooxygenase-2 (COX-2) processes simultaneous input signals within a complex interaction network. We find that changes in input levels affect the amount of information transmitted by the network, as does the correlation between those inputs. This, and the allosteric regulation of COX-2 by its substrates, allows it to act as a signal integrator that is most sensitive to changes in relative input levels.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Transdução de Sinais/fisiologia , Algoritmos , Regulação Alostérica/fisiologia , Biologia Computacional/métodos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/fisiologia , Teoria da Informação , Cinética , Modelos Biológicos , Mapas de Interação de Proteínas/fisiologia , Biologia de Sistemas/métodos
2.
Endocr J ; 66(8): 691-699, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31105125

RESUMO

The cyclooxygenase2 (COX-2) enzyme catalyzes the first step of prostanoid biosynthesis, and is known for its crucial role in the pathogenesis of several inflammatory diseases including type 2 diabetes mellitus (T2DM). Although a variety of studies revealed that COX-2 played a role in the IL-1ß induced ß cell dysfunction, the molecular mechanism remains unclear. Here, using a cDNA microarray and in silico analysis, we demonstrated that inflammatory responses were upregulated in human T2DM islets compared with non-diabetic (ND) islets. COX-2 expression was significantly enhanced in human T2DM islets, correlated with the high inflammation level. PGE2, the catalytic product of COX-2, downregulated the functional gene expression of PDX1, NKX6.1, and MAFA and blunted the glucose induced insulin secretion of human islets. Conversely, inhibition of COX-2 activity by a pharmaceutical inhibitor prevented the ß-cell dysfunction induced by IL-1ß. COX-2 inhibitor also abrogated the IL-1ß autostimulation in ß cells, which further resulted in reduced COX-2 expression in ß cells. Together, our results revealed that COX-2/PGE2 signaling was involved in the regulation of IL-1ß autostimulation, thus forming an IL-1ß/COX-2/PGE2 pathway loop, which may result in the high inflammation level in human T2DM islets and the inflammatory impairment of ß cells. Breaking this IL-1ß/COX-2/PGE2 pathway loop provides a potential therapeutic strategy to improve ß cell function in the treatment of T2DM patients.


Assuntos
Ciclo-Oxigenase 2/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Dinoprostona/fisiologia , Interleucina-1beta/fisiologia , Ilhotas Pancreáticas/fisiopatologia , Adulto , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Dinoprostona/metabolismo , Retroalimentação Fisiológica/fisiologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Transdução de Sinais/fisiologia
3.
Indian J Dent Res ; 30(1): 102-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30900666

RESUMO

Background and Aim: Oral cancer is a major health problem in South East Asia. The immunohistochemical (IHC) overexpression of COX-2 in squamous cell carcinoma is well documented. This IHC study was undertaken to understand the COX-2 expression in different grades of oral squamous cell carcinoma (OSCC) and to compare the COX-2 expression in OSCC and normal mucosa. Material and Methods: A total of 30 cases of OSCC and 10 cases of normal mucosa and positive control colon cancer were studied for IHC expression of COX-2. Of the 30 cases studied 10 cases each of well, moderately and poorly differentiated carcinoma were studied. COX-2 staining was evaluated on the basis of presence or absence of the positive tumor cells and percentage of positive tumor cells. Statistical Analysis: The various statistical tests used in this study were t-test and Chi-square test which was carried out using SPSS for Windows 22.0.0 and Minitab version 17.1.0 software package. Results: There was significant increase in COX-2 staining intensity from well to poorly differentiated OSCC. Significant difference was observed in staining intensity between moderately and poorly differentiated SCC. The percentage of positive tumor cells were high in poorly differentiated SCC compared to well and moderately differentiated OSCC. No significant expression of COX-2 was noted in normal mucosa. Interpretation and Conclusion: Our results revealed that the COX-2 enzymes were expressed, suggesting that they play complementary roles during oral carcinogenesis. In near future researches on administration of chemoradiation therapy combined with COX-2 should be evaluated to improve therapy response.


Assuntos
Carcinoma de Células Escamosas/enzimologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica , Neoplasias Bucais/enzimologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Distribuição de Qui-Quadrado , Ciclo-Oxigenase 2/fisiologia , Humanos , Imuno-Histoquímica , Terapia de Alvo Molecular , Mucosa Bucal/enzimologia , Neoplasias Bucais/patologia , Neoplasias Bucais/terapia , Gradação de Tumores
4.
Naunyn Schmiedebergs Arch Pharmacol ; 392(4): 437-450, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30552456

RESUMO

Various studies have confirmed that prostaglandins (PG) alter the bladder motor activity and micturition reflex in both human and animals. However, no sufficient data is reported about the effect of cyclooxygenase (COX) inhibitors neither in normal bladder physiology nor in pathological conditions. This study aims to compare the potential effects of some COX inhibitors with varying COX-1/COX-2 selectivities (indomethacin, ketoprofen, and diclofenac) with that of the selective COX-2 inhibitor (DFU) on bladder function. The role played by some PGs and their receptors in controlling detrusor muscle function in normal condition and in cystitis is also studied. Organ bath experiments were performed using isolated rat detrusor muscle. Direct and neurogenic contractions were induced using ACh and electric stimulation (EFS), respectively. A model of hemorrhagic cystitis was induced by single injection of cyclophosphamide (300 mg/kg) in rats, and confirmed by histophathological examination. Results are expressed as mean ± SEM of 5-9 rats. Alprostadil and iloprost (1 nM- 10 µM) concentration-dependently potentiated ACh (100 µM)- and EFS (4 Hz)-induced contraction, with maximum potentiation of 40.01 ± 5.29 and 27.59 ± 6.64%, respectively, in case of ACh contractions. In contrast, ONO-AE1-259 (selective EP2 agonist, 1 nM-10 µM) inhibited muscle contraction. SC51322 (EP1-antagonist, 10 µM) and RO1138452 (IP antagonist, 10 µM) inhibited both direct and neurogenic responses. Hemorrhagic cystitis reduced both ACh and EFS responses as well as the potentiatory effect of iloprost and the inhibitory effect of RO1138452 on ACh contractions. ONO-AE3-237 (DP1 antagonist, 1 µM) significantly potentiated contractions in cystitis but showed no effect in normal bladder. A significant inhibition of contractile response was observed in presence of indomethacin, ketoprofen, and diclofenac at all tested concentrations (20, 50, and 100 µM). Highest effect was induced by diclofenac. The effect of these COX inhibitors on EFS contractions was intensified in case of cystitis, indomethacin being the most potent. Atropine (1 nM) significantly reduced indomethacin effect on ACh contraction only in normal rats. On the other hand, DFU (10-6 M) significantly potentiated the contractile effect of ACh in case of cystitis although it showed no effect in normal rats. EP1 receptors seem to play an important role in rat bladder contractility. DP1 receptors as COX-2, on the other hand, gain an important role only in case of cystitis. The use of non-selective COX inhibitors in cystitis may be associated with bladder hypoactivity; selective COX-2 inhibitors may be a safer option.


Assuntos
Inibidores de Ciclo-Oxigenase/efeitos adversos , Cistite/patologia , Músculo Liso/efeitos dos fármacos , Receptores de Prostaglandina/antagonistas & inibidores , Bexiga Urinária/efeitos dos fármacos , Animais , Ciclo-Oxigenase 1/fisiologia , Ciclo-Oxigenase 2/fisiologia , Ciclofosfamida , Cistite/induzido quimicamente , Cistite/fisiopatologia , Modelos Animais de Doenças , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/patologia , Músculo Liso/fisiologia , Ratos Wistar , Receptores de Prostaglandina/fisiologia , Bexiga Urinária/patologia , Bexiga Urinária/fisiologia
5.
Nutr Cancer ; 70(6): 840-850, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273003

RESUMO

Many cancers and pre-cancerous lesions convert membrane-bound arachidonic acid (AA) to eicosanoids that promote the survival, growth, and spread of cancer. In contrast, the long-chain omega-3s eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can competitively inhibit AA's interaction with the enzymes that give rise to eicosanoids, while acting as precursors for alternative eicosanoids which oppose cancer development and growth. Hence, minimizing the AA content of cancer membranes, while boosting that of EPA and DHA, is a rational strategy for cancer prevention and control. The former goal can be achieved by eating a plant-based diet (inherently free of AA); by avoiding foods high in linoleic acid; by down-regulating the expression of delta-6-desaturase (D6D), rate-limiting for the conversion of linoleic acid to AA; and by competitively decreasing flux of linoleic acid through D6D with a high intake of alpha-linolenic acid (ALA) from flaxseed. ALA and DHA, potent agonists for the farnesoid X receptor, can be expected to suppress D6D transcription, and AMP-activated kinase (AMPK) activators and a cholesterol-free diet also have potential in this regard. Hence, a plant-based diet low in linoleic acid, complemented by an ample intake of flaxseed and supplemental fish oil, with or without metformin and other D6D-antagonist agents, may aid prevention and control of some cancers.


Assuntos
Ácido Araquidônico/análise , Membrana Celular/química , Neoplasias/prevenção & controle , Ácido Araquidônico/metabolismo , Ciclo-Oxigenase 2/fisiologia , Dieta , Ácidos Graxos Dessaturases/antagonistas & inibidores , Óleos de Peixe/administração & dosagem , Linho , Humanos , Ácido Linoleico/administração & dosagem , Ácido Linoleico/metabolismo , Neoplasias/química , Receptores Citoplasmáticos e Nucleares/fisiologia
6.
J Leukoc Biol ; 104(6): 1173-1186, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30145840

RESUMO

Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However, the molecular and cellular mechanism of this provocative adverse effect is unclear. Our goal was to determine whether carprofen (CAP) impedes splenic leukocyte-directed acute inflammation-resolving response in cardiac injury. After subacute CAP treatment, mice were subjected to permanent coronary ligation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quantitated using flow cytometry pre- and 24 h post-MI. The inflammation resolution mediators were quantified using mass spectrometry while splenocardiac apoptosis and leukocyte phagocytosis were measured by immunofluorescence and ImageStream, respectively. Subacute CAP treatment promoted strain and cardiac dysfunction before MI and coronary occlusion showed signs of acute HF in CAP and MI-controls. Subacute CAP-injected mice had pre-activated splenic neutrophils, an over activated "don't eat me" signal (CD47) with reduced total Mϕs (F4/80+ ) and reparative Mϕs (F4/80/Ly6Clo /CD206) compared with control in LV and spleen. Post-MI, CAP pre-activated neutrophils (Ly6G+ ) were intensified and reduced reparative neutrophils (Ly6G+ /CD206+ ) and Mϕs (F4/80/Ly6Clo ) in LV was indicative of non-resolving inflammation compared with MI-control. Subacute CAP treatment deferred neutrophil phagocytosis functions in the spleen and LV and was more evident post-MI compared with MI-control. CAP pre-activated splenic neutrophils that tailored the Mϕ phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane in post-MI setting. Further, CAP reduced cardiac-protective epoxyeicosatrienoic acids and over amplified pyrogenic inflammatory cytokines and reduced reparative cytokines, thereby non-resolving inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Carbazóis/toxicidade , Ventrículos do Coração/efeitos dos fármacos , Inflamação/induzido quimicamente , Leucócitos/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Baço/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Carbazóis/farmacologia , Ciclo-Oxigenase 1/fisiologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/fisiologia , Eicosanoides/metabolismo , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/imunologia , Ventrículos do Coração/fisiopatologia , Inflamação/etiologia , Mediadores da Inflamação/metabolismo , Leucócitos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/patologia , Ativação de Neutrófilo/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Prostaglandinas/metabolismo , Baço/imunologia , Baço/fisiopatologia
7.
Sci Rep ; 8(1): 10005, 2018 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-29968808

RESUMO

The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a with IC50 value and the selectivity for COX-2 0.6 nM and 1666, respectively. The MTD of (S)-3a was 2000 mg kg-1 and its pharmacokinetic studies in rat showed t1/2 7.5 h. This compound reversed acetic acid induced analgesia and carragennan induced inflammation by 50% and 25% in rat when used at a dose 10 mg kg-1. Mechanistically, it was found that compound (S)-3a inhibits COX-2. Overall, the combination of physico-chemical and biological experiments facilitated the development of a new lead molecule to anti-inflammatory drug.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas/métodos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/fisiologia , Inibidores de Ciclo-Oxigenase 2/síntese química , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Masculino , Dor/tratamento farmacológico , Ratos , Ratos Wistar , Relação Estrutura-Atividade
8.
Neuromolecular Med ; 20(1): 133-146, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29468499

RESUMO

Autism is a neurodevelopmental disorder characterized by deficits in qualitative impairments in communication, repetitive and social interaction, restricted, and stereotyped patterns of behavior. Resveratrol has been extensively studied pharmacologically and biologically and has anti-inflammatory, antioxidant, and neuroprotective effects on neuronal damage in neurodegenerative disorders. The BTBR T+ Itpr3tf/J (BTBR) autistic mouse model has been explored for treatment of autism, which shows low reciprocal social interactions, impaired juvenile play, and decreased social approach. Here, we explored whether resveratrol treatment decreases neuroimmune dysregulation mediated through toll-like receptor (TLR4) and nuclear factor-κB (NF-κB) signaling pathway in BTBR mice. We investigated the effect of resveratrol treatment on TLR2, TLR3, TLR4, NF-κB, and inducible nitric oxide synthase (iNOS or NOS2) levels in CD4 spleen cells. We also assessed the effect of resveratrol treatment on TLR2, TLR3, TLR4, NF-κB, iNOS, and cyclooxygenase (COX-2) mRNA expression levels in the brain tissue. We further explored TLR2, TLR4, NF-κB, iNOS, and COX-2 protein expression levels in the brain tissue. Resveratrol treatment on BTBR mice significantly decreased CD4+TLR2+, CD4+TLR3+, CD4+TLR4+ CD4+NF-κB+, and CD4+iNOS+ levels in spleen cells. Resveratrol treatment on BTBR mice decreased TLR2, TLR3, TLR4, NF-κB, iNOS, and COX-2 mRNA expression levels in brain tissue. Moreover, resveratrol treatment resulted in decreased protein expression of TLR2, TLR3, TLR4, NF-κB, iNOS, and COX-2 in brain tissue. Taken together, these results indicate that resveratrol treatment improves neuroimmune dysregulation through the inhibition of proinflammatory mediators and TLRs/NF-κB transcription factor signaling, which might be help devise future therapies for neuroimmune disorders.


Assuntos
Transtorno Autístico/tratamento farmacológico , Ciclo-Oxigenase 2/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Óxido Nítrico Sintase Tipo II/fisiologia , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/fisiologia , Animais , Transtorno Autístico/metabolismo , Química Encefálica/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Avaliação Pré-Clínica de Medicamentos , Receptores de Inositol 1,4,5-Trifosfato , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , NF-kappa B/fisiologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Especificidade de Órgãos , Resveratrol/farmacologia , Baço , Receptores Toll-Like/biossíntese , Receptores Toll-Like/genética
9.
Transl Res ; 196: 42-61, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29421522

RESUMO

A plentiful literature has linked colorectal cancer (CRC) to inflammation and prostaglandin-endoperoxide synthase (PTGS)2 expression. Accordingly, several nonsteroidal antiinflammatory drugs (NSAIDs) have been tested often successfully in CRC chemoprevention despite their different ability to specifically target PTGS2 and the low or null expression of PTGS2 in early colon adenomas. Some observational studies showed an increased survival for patients with CRC assuming NSAIDs after diagnosis, but no clinical trial has yet demonstrated the efficacy of NSAIDs against established CRC, where PTGS2 is expressed at high levels. The major limits for the application of NSAIDs, or specific PTGS2 inhibitors, as adjuvant drugs in CRC are (1) a frequent confusion about the physiological role of PTGS1 and PTGS2, reflecting in CRC pathology and therapy; (2) the presence of unavoidable side effects linked to the intrinsic function of these enzymes; (3) the need of established criteria and markers for patient selection; and (4) the evaluation of the immunomodulatory potential of PTGS2 inhibitors as possible adjuvants for immunotherapy. This review has been written to rediscover the multifaceted potential of PTGS2 targeting, hoping it could act as a starting point for a new and more aware application of NSAIDs against CRC.


Assuntos
Neoplasias Colorretais/prevenção & controle , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/fisiologia , Focos de Criptas Aberrantes/prevenção & controle , Animais , Quimioprevenção , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Sistema Imunitário/fisiologia , Estruturas Linfoides Terciárias/prevenção & controle
10.
Pharmacol Res ; 133: 236-249, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29309904

RESUMO

Cyclooxygenase-2 (COX-2) derived-prostanoids participate in the altered vascular function and mechanical properties in cardiovascular diseases. We investigated whether regulator of calcineurin 1 (Rcan1) participates in vascular contractility and stiffness through the regulation of COX-2. For this, wild type (Rcan1+/+) and Rcan1-deficient (Rcan1-/-) mice untreated or treated with the COX-2 inhibitor rofecoxib were used. Vascular function and structure were analysed by myography. COX-2 and phospo-p65 expression were studied by western blotting and immunohistochemistry and TXA2 production by ELISA. We found that Rcan1 deficiency increases COX-2 and IL-6 expression and NF-κB activation in arteries and vascular smooth muscle cells (VSMC). Adenoviral-mediated re-expression of Rcan1.4 in Rcan1-/- VSMC normalized COX-2 expression. Phenylephrine-induced vasoconstrictor responses were greater in aorta from Rcan1-/- compared to Rcan1+/+ mice. This increased response were diminished by etoricoxib, furegrelate, SQ 29548, cyclosporine A and parthenolide, inhibitors of COX-2, TXA2 synthase, TP receptors, calcineurin and NF-κB, respectively. Endothelial removal and NOS inhibition increased phenylephrine responses only in Rcan1+/+ mice. TXA2 levels were greater in Rcan1-/- mice. In small mesenteric arteries, vascular function and structure were similar in both groups of mice; however, vessels from Rcan1-/- mice displayed an increase in vascular stiffness that was diminished by rofecoxib. In conclusion, our results suggest that Rcan1 might act as endogenous negative modulator of COX-2 expression and activity by inhibiting calcineurin and NF-kB pathways to maintain normal contractility and vascular stiffness in aorta and small mesenteric arteries, respectively. Our results uncover a new role for Rcan1 in vascular contractility and mechanical properties.


Assuntos
Aorta Torácica/fisiologia , Ciclo-Oxigenase 2/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Artérias Mesentéricas/fisiologia , Proteínas Musculares/fisiologia , Músculo Liso Vascular/fisiologia , Animais , Proteínas de Ligação ao Cálcio , Células Cultivadas , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Contração Muscular , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/fisiologia
11.
Am J Pathol ; 188(2): 450-460, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29154961

RESUMO

The incorporation of endothelial progenitor cells (EPCs) into newly developing blood vessels contributes to the vascularization of endometriotic lesions. We analyzed whether cyclooxygenase (COX)-2 signaling regulates this vasculogenic process. Endometriotic lesions were surgically induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN [Tie2/green fluorescent protein (GFP)] 287 Sato mice. The animals received ß-estradiol 17-valerate once a week and were treated daily with the selective COX-2 inhibitor parecoxib (25 mg/kg) or vehicle (control) for 7 and 28 days. Analyses involved the determination of lesion growth, cyst formation, homing of GFP+/Tie2+ EPCs, numbers of circulating EPCs, vascularization, cell proliferation, apoptosis, and immune cell infiltration by means of high-resolution ultrasonography, caliper measurements, flow cytometry, histologic analysis, and immunohistochemical analysis. In parecoxib-treated mice, blood circulating EPCs were higher, but numbers of recruited EPCs in endometriotic lesions were significantly lower when compared with controls. This finding was associated with an impaired early vascularization and stromal tissue growth as well as reduced glandular secretory activity of the lesions. Parecoxib-treated lesions further contained less proliferating and more apoptotic cells and exhibited lower numbers of infiltrating macrophages and neutrophilic granulocytes. These findings demonstrate that the inhibition of COX-2 suppresses vasculogenesis in endometriotic lesions, which may contribute to an impaired lesion vascularization and growth.


Assuntos
Ciclo-Oxigenase 2/fisiologia , Endometriose/patologia , Células Progenitoras Endoteliais/patologia , Neovascularização Patológica/prevenção & controle , Animais , Apoptose/fisiologia , Proliferação de Células/fisiologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Endometriose/diagnóstico por imagem , Endometriose/enzimologia , Endometriose/imunologia , Endométrio/irrigação sanguínea , Endométrio/patologia , Endotélio Vascular/patologia , Feminino , Isoxazóis/farmacologia , Camundongos Endogâmicos , Microvasos/patologia , Neovascularização Patológica/enzimologia , Neovascularização Patológica/patologia , Transdução de Sinais/fisiologia , Ultrassonografia
12.
Chemosphere ; 190: 124-134, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28987401

RESUMO

Long-term exposure to fine particulate matter (PM2.5) has been reported to be closely associated with the neuroinflammation and synaptic dysfunction, but the mechanisms underlying the process remain unclear. Cyclooxygenase-2 (COX-2) is a key player in neuroinflammation, and has been also implicated in the glutamatergic excitotoxicity and synaptic plasticity. Thus, we hypothesized that COX-2 was involved in PM2.5-promoted neuroinflammation and synaptic dysfunction. Our results revealed that PM2.5 elevated COX-2 expression in primary cultured hippocampal neurons and increased the amplitude of field excitatory postsynaptic potentials (fEPSPs) in hippocampal brain slices. And the administration of NS398 (a COX-2 inhibitor) prevented the increased fEPSPs. PM2.5 also induced intracellular reactive oxygen species (ROS) generation accompanied with glutathione (GSH) depletion and the loss of mitochondrial membrane potential (MMP), and the ROS inhibitor, N-acetyl-L-cystein (NAC) suppressed the COX-2 overexpression and the increased fEPSPs. Furthermore, the nuclear factor kappa B (NF-κB) was involved in ROS-induced COX-2 and fEPSP in response to PM2.5 exposure. These findings indicated that PM2.5 activated COX-2 expression and enhanced the synaptic transmission through ROS-NF-κB pathway, and provided possible biomarkers and specific interventions for PM2.5-induced neurological damage.


Assuntos
Ciclo-Oxigenase 2/fisiologia , NF-kappa B/metabolismo , Material Particulado/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Transmissão Sináptica , Animais , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Hipocampo/citologia , Inflamação/etiologia , Camundongos , Neurônios/patologia , Material Particulado/farmacologia , Transmissão Sináptica/efeitos dos fármacos
13.
Cancer Lett ; 412: 69-80, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28964785

RESUMO

Metastasis and chemoresistance are two major causes of breast cancer death. We show here that the chemokine receptor CXCR2 was overexpressed in breast cancer cell lines and tissues. CXCR2 promoted anti-apoptosis, anti-senescence, and epithelial-to-mesenchymal transition (EMT) of breast cancer cells, leading to the enhanced metastasis and chemoresistance. Further study suggested that AKT1 and cyclooxygenase-2 (COX2; PTGS2) might mediate the CXCR2 signaling to inversely control the breast cancer metastasis and chemoresistance through the regulation of EMT, apoptosis, and senescence. Analyses of clinical data indicate that the high expression of CXCR2 was correlated with the high expression of COX2 and the low expression of AKT1, P85α, E-cadherin, and ß-catenin in cancer tissues. Poor outcomes were associated with the high expression of CXCR2 or COX2 while favorable survivals were associated with the high expression of P85α, AKT1, or E-cadherin in all cancer patients. Cox multivariate analysis demonstrated that CXCR2, COX2, and AKT1 could be independent predictors for disease free survivals. All these data suggest that CXCR2 promotes breast cancer metastasis and chemoresistance via suppressing AKT1 and activating COX2. Thus, antagonists of the CXCR2 signaling molecules may be used to treat breast cancer patients particularly with high metastasis and chemoresistance.


Assuntos
Neoplasias da Mama/patologia , Ciclo-Oxigenase 2/fisiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Receptores de Interleucina-8B/fisiologia , Apoptose , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Humanos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Receptores de Interleucina-8B/antagonistas & inibidores
14.
AAPS J ; 19(6): 1779-1790, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28842850

RESUMO

Metastasis remains the leading cause of death from lung carcinoma. It is urgent to find safe and efficient pre-metastasis preventive agents for cancer survivors. We isolated a flavonoid glycoside, hexamethoxy flavanone-o-[rhamnopyranosyl-(1 â†’ 4)-rhamnopyranoside (HMFRR), from the traditional Chinese medicine (TCM) Murraya paniculata (L.) that can effectively inhibit the adhesion, migration, and invasion of lung adenocarcinoma A549 cells in vitro. Molecular and cellular studies demonstrated that HMFRR significantly downregulated the expressions of cell adhesion-related and invasion-related molecules such as integrin ß1, EGFR, COX-2, MMP-2, and MMP-9 proteins. Additionally, HMFRR effectively downregulated the expressions of epithelial-mesenchymal transition (EMT) markers (N-cadherin and vimentin) and upregulated that of E-cadherin. Moreover, these inhibitions were mediated by interrupting STAT3/NF-κB/COX-2 and EGFR/PI3K/AKT signaling pathways. Furthermore, HMFRR counteracted the expressions of cell adhesion molecules (ICAM-1, VCAM-1, and E-selectin) stimulated by interleukin-1ß in human pulmonary microvascular endothelial cells (HPMECs). As a result, HMFRR interrupted the adhesion of A549 cells to HPMECs. Collectively, these results indicate that HMFRR may become a good candidate for cancer metastatic chemopreventive agents by interrupting the STAT3/NF-κB/COX-2 and EGFR signaling pathways.


Assuntos
Anticarcinógenos/farmacologia , Ciclo-Oxigenase 2/fisiologia , Receptores ErbB/fisiologia , Flavonoides/farmacologia , Glicosídeos/farmacologia , Murraya/química , NF-kappa B/fisiologia , Metástase Neoplásica/prevenção & controle , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Medicina Tradicional Chinesa
15.
Br J Pharmacol ; 174(22): 4087-4098, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28675448

RESUMO

BACKGROUND AND PURPOSE: The side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I2 synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE2 from COX-derived PGH2 . This enzyme is induced under inflammatory conditions and constitutes an attractive target for novel anti-inflammatory drugs. However, it is not known whether mPGES-1 inhibitors could be devoid of cardiovascular side effects. The aim of this study was to compare, in vitro, the effects of mPGES-1 and COX-2 inhibitors on vascular tone in human blood vessels. EXPERIMENTAL APPROACH: The vascular tone and prostanoid release from internal mammary artery (IMA) and saphenous vein (SV) incubated for 30 min with inhibitors of mPGES-1 or COX-2 were investigated under normal and inflammatory conditions. KEY RESULTS: In inflammatory conditions, mPGES-1 and COX-2 proteins were more expressed, and increased levels of PGE2 and PGI2 were released. COX-2 and NOS inhibitors increased noradrenaline induced vascular contractions in IMA under inflammatory conditions while no effect was observed in SV. Interestingly, the mPGES-1 inhibitor significantly reduced (30-40%) noradrenaline-induced contractions in both vessels. This effect was reversed by an IP (PGI2 receptor) antagonist but not modified by NOS inhibition. Moreover, PGI2 release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE2 release. CONCLUSIONS AND IMPLICATIONS: In contrast to COX-2 inhibition, inhibition of mPGES-1 reduced vasoconstriction by increasing PGI2 synthesis. Targeting mPGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors. LINKED ARTICLES: This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.


Assuntos
Epoprostenol/fisiologia , Artéria Torácica Interna/fisiologia , Prostaglandina-E Sintases/fisiologia , Veia Safena/fisiologia , Idoso , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/fisiologia , Inibidores de Ciclo-Oxigenase/farmacologia , Epoprostenol/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Artéria Torácica Interna/efeitos dos fármacos , Artéria Torácica Interna/metabolismo , Pessoa de Meia-Idade , Norepinefrina/farmacologia , Prostaglandina-E Sintases/antagonistas & inibidores , Prostaglandina-E Sintases/metabolismo , Veia Safena/efeitos dos fármacos , Veia Safena/metabolismo , Tiofenos/farmacologia , Vasoconstritores/farmacologia
16.
PLoS One ; 12(5): e0176527, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28464042

RESUMO

Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/µL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.


Assuntos
Ciclo-Oxigenase 2/fisiologia , Inibidores de Ciclo-Oxigenase/uso terapêutico , Infecções por HIV/enzimologia , Piridinas/uso terapêutico , Sulfonas/uso terapêutico , Linfócitos T/fisiologia , Adulto , Progressão da Doença , Etoricoxib , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Imunidade Celular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Vacinas Pneumocócicas/farmacologia , Toxoide Tetânico/farmacologia
17.
Oncogene ; 36(31): 4415-4426, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28346420

RESUMO

Cyclooxygenase (COX)-2 is upregulated in hepatocellular carcinoma (HCC). However, the direct causative effect of COX-2 in spontaneous HCC formation remains unknown. We thus investigate the role and molecular pathogenesis of COX-2 in HCC by using liver-specific COX-2 transgenic (TG) mice. We found spontaneous HCC formation with elevated inflammatory infiltrates and neovessels in male TG mice (3/21, 14.3%), but not in any of male WT mice (0/19). Reduced representation bisulfite sequencing (RRBS) and gene expression microarrays were performed in the HCC tumor and non-HCC liver tissues to investigate the molecular mechanisms of COX-2-driven HCC. By RRBS, DNA promoter hypermethylation was identified in HCC from TG mice. Induction of promoter hypermethylation was associated with reduced tet methylcytosine dioxygenase 1 (TET1) expression by COX-2. TET1 could catalyze the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5hmC) and prevents DNA hypermethylation. In keeping with this, loss of 5hmC was demonstrated in COX-2-induced HCC. Consistently, COX-2 overexpression in human HCC cell lines could reduce both TET1 expression and 5hmc levels. Integrative analyses of DNA methylation and gene expression profiles further identified significantly downregulated genes including LTBP1, ADCY5 and PRKCZ by promoter methylation in COX-2-induced HCC. Reduced expression of LTBP1, ADCY5 and PRKCZ by promoter hypermethylation was further validated in human HCCs. Bio-functional investigation revealed that LTBP1 inhibited cell proliferation in HCC cell lines, suggesting its potential role as a tumor suppressor in HCC. Gene expression microarrays revealed that signaling cascades (AKT (protein kinase B), STK33 (Serine/Threonine kinase 33) and MTOR (mechanistic target of rapamycin) pathways) were enriched in COX-2-induced HCC. In conclusion, this study demonstrated for the first time that enhanced COX-2 expression in hepatocytes is sufficient to induce HCC through inducing promoter hypermethylation by reducing TET1, silencing tumor-suppressive genes and activating key oncogenic pathways. Inhibition of COX-2 represents a mechanism-based target for HCC prevention.


Assuntos
Carcinoma Hepatocelular/etiologia , Ciclo-Oxigenase 2/fisiologia , Neoplasias Hepáticas/etiologia , Fígado/enzimologia , Animais , Linhagem Celular Tumoral , Metilação de DNA , Proteínas de Ligação a DNA/fisiologia , Humanos , Proteínas de Ligação a TGF-beta Latente/fisiologia , Masculino , Camundongos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/fisiologia
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 42(2): 139-146, 2017 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-28255114

RESUMO

OBJECTIVE: To explore the expressions of miR-26b and cyclooxygenase (COX)-2 in different grades of gliomas and the effect of miR-26b on glioma cell proliferation, invasion and migration.
 Methods: Western blot and Real-time quantitative PCR (qRT-PCR) were used to detect the expression levels of miR-26b and COX-2 in different grades of gliomas. Human glioma cells were transfected with miR-26b mimics. qRT-PCR was employed to detect the mRNA expressions of miR-26b and COX-2 after miR-26b mimics transfection, while dual-luciferase reporter assay was used to investigate the regulatory effect of miR-26b on COX-2. Cell counting kit-8 (CCK8), trans-well invasion assay and scratch assay were used to detect the proliferation, invasion and migration of human U87 glioma cells after miR-26b mimic transfection, respectively. The antitumor effect of miR-26b was verified by evaluating the volume and weight of tumor in nude mice.
 Results: With the increase in tumor grades, the expression of miR-26b was significantly decreased (P<0.05), while COX-2 expression was increased (P<0.001). Dual luciferase assay confirmed that miR-26b could directly regulate the protein expression of COX-2. MiR-26b mimics could significantly reduce the expression of COX-2 (P<0.05) and suppress the proliferation, invasion and migration of glioma cell (P<0.05). The volume and weight of tumor in MiR-26b mimics transfection group were smaller than those in the control group.
 Conclusion: Overexpression of miR-26b may inhibit proliferation, invasion, and migration of glioma by suppressing the expression of COX-2. Therefore, the miR-26b/COX-2 pathway might be a therapeutic target in glioma.


Assuntos
Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/fisiologia , Glioma/química , Glioma/fisiopatologia , MicroRNAs/química , MicroRNAs/genética , MicroRNAs/fisiologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Humanos , Camundongos Nus , Gradação de Tumores , Invasividade Neoplásica/genética , Invasividade Neoplásica/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Transfecção
19.
Proc Natl Acad Sci U S A ; 114(5): 1117-1122, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28096371

RESUMO

In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)-mediated inhibition of activated PD-1+ T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti-PD-L1 and -PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow-derived myeloid cells. Tumor-induced expression of PD-L1 was limited to F4/80+ macrophages and Ly-6C+ myeloid-derived suppressor cells. These PD-L1-expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1+ cells isolated from tumor-bearing mice also exerted morphology of tumor-associated macrophages and expressed high levels of prostaglandin E2 (PGE2)-forming enzymes microsomal PGE2 synthase 1 (mPGES1) and COX2. Inhibition of PGE2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE2 pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.


Assuntos
Antígeno B7-H1/biossíntese , Células da Medula Óssea/metabolismo , Ciclo-Oxigenase 2/fisiologia , Dinoprostona/fisiologia , Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Prostaglandina-E Sintases/fisiologia , Animais , Antígeno B7-H1/genética , Comunicação Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Hidroxiprostaglandina Desidrogenases/biossíntese , Hidroxiprostaglandina Desidrogenases/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos NOD , Camundongos SCID , Antagonistas de Prostaglandina/farmacologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
20.
J Cereb Blood Flow Metab ; 37(3): 1060-1068, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27178425

RESUMO

Cortical spreading depression (CSD) is considered a significant phenomenon for human neurological conditions and one of its key signatures is the development of persistent cortical oligemia. The factors underlying this reduction in cerebral blood flow (CBF) remain incompletely understood but may involve locally elaborated vasoconstricting eicosanoids. We employed laser Doppler flowmetry in urethane-anesthetized rats, together with a local pharmacological blockade approach, to test the relative contribution of cyclooxygenase (COX)-derived prostanoids to the oligemic response following CSD. Administration of the non-selective COX inhibitor naproxen completely inhibited the oligemic response. Selective inhibition of COX-1 with SC-560 preferentially reduced the early reduction in CBF while selective COX-2 inhibition with NS-398 affected only the later response. Blocking the action of thromboxane A2 (TXA2), using the selective thromboxane synthase inhibitor ozagrel, reduced only the initial CBF decrease, while inhibition of prostaglandin F2alpha action, using the selective FP receptor antagonist AL-8810, blocked the later phase of the oligemia. Our results suggest that the long-lasting oligemia following CSD consists of at least two distinct temporal phases, mediated by preferential actions of COX-1- and COX-2-derived prostanoids: an initial phase mediated by COX-1 that involves TXA2 followed by a later phase, mediated by COX-2 and PGF2alpha.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Ciclo-Oxigenase 1/fisiologia , Ciclo-Oxigenase 2/fisiologia , Prostaglandinas/fisiologia , Animais , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprosta/fisiologia , Fluxometria por Laser-Doppler , Ratos , Tromboxano A2/fisiologia , Fatores de Tempo
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