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1.
Anticancer Res ; 41(3): 1307-1314, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788722

RESUMO

BACKGROUND/AIM: Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) is a terminal enzyme in PGE2 synthesis and highly expressed in several cancers. In this study, to reveal the involvement of mPGES-1 in skin carcinogenesis, the effect of mPGES-1 deficiency on two-stage skin carcinogenesis in mice was investigated. MATERIALS AND METHODS: A two-stage skin carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a promoter was applied on mPGES-1 knockout (KO) mice and littermate wild-type mice of a Balb/c genetic background. RESULTS: DMBA/TPA-induced skin carcinogenesis was suppressed in mPGES-1 KO mice. The induction of IL-17 and other inflammatory cytokines by TPA was also suppressed by mPGES-1 deficiency, although DMBA-induced apoptosis was not affected. CONCLUSION: mPGES-1 promotes chemically induced skin carcinogenesis and might play an important role in the TPA-induced promotion phase of the two-stage skin carcinogenesis model. mPGES-1 inhibition may be a therapeutic target for skin cancer.


Assuntos
Prostaglandina-E Sintases/fisiologia , Neoplasias Cutâneas/prevenção & controle , 9,10-Dimetil-1,2-benzantraceno , Animais , Apoptose/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Citocinas/biossíntese , Dinoprostona/análise , Camundongos , Camundongos Endogâmicos BALB C , Prostaglandina-E Sintases/deficiência , Prostaglandina-E Sintases/genética , Neoplasias Cutâneas/induzido quimicamente , Acetato de Tetradecanoilforbol
2.
Brain Res ; 1750: 147153, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33049240

RESUMO

Prostaglandin E2 (PGE2) is a lipid mediator which plays a role in the generation of inflammatory and neuropathic pain. In the peripheral nervous system, PGE2 sensitizes nociceptive afferent neurons through E-prostanoid (EP) receptors. In the central nervous system, PGE2 modulates pain sensitivity and contributes to the development of neuropathic pain. However, the distribution of PGE2 and EP receptors in the spinal cord remains unclear. In the present study, we examined the expression of PGE2 synthases (microsomal PGE synthase [mPGES]-1, mPGES-2, and cytosolic PGE synthase [cPGES]) and EP receptors (EP1-4) in a rat model of neuropathic pain. We identified that mPGES-1 mRNA was upregulated in spinal endothelial cells after nerve injury and exhibited co-localization with cyclooxygenase-2 (COX-2). We detected that mPGES-2 mRNA and cPGES mRNA were expressed in spinal neurons and noted that their expression level was not affected by nerve injury. With respect to EP receptors, EP2 mRNA and EP4 mRNA were expressed in spinal neurons in the dorsal horn. EP3 mRNA was expressed in motor neurons, whereas EP1 mRNA was not detected in the spinal cord. Intrathecal injection of tumor necrosis factor alpha (TNFα) upregulated mPGES-1 mRNA in blood vessels in the spinal cord. Intrathecal injection of a TNFα-neutralizing antibody partially inhibited the upregulation of mPGES-1 mRNA after nerve injury. These results indicate that PGE2 is synthesized by COX-2/mPGES-1 in spinal endothelial cells after nerve injury. These results suggest that in neuropathic pain condition, endothelial cell-derived PGE2 may act on EP2 and EP4 receptors on spinal neurons and modulate pain sensitivity.


Assuntos
Neuralgia/fisiopatologia , Prostaglandina-E Sintases/metabolismo , Receptores de Prostaglandina E/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Expressão Gênica/genética , Oxirredutases Intramoleculares/metabolismo , Masculino , Limiar da Dor/efeitos dos fármacos , Prostaglandina-E Sintases/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E/fisiologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Medula Espinal/fisiologia
3.
Biochem Biophys Res Commun ; 521(2): 347-352, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31668810

RESUMO

We had previously reported a prostaglandin E synthase (bmPGES) in the silkworm Bombyx mori that catalyzes the isomerization of PGH2 to PGE2. The present study aimed to provide a genome-editing characterization of bmPGES in B. mori. Results showed bmPGES gene disruption to result in a reduced content of PGE2. The change affected the expression of chorion genes and egg formation in silkworms. Collectively, the results indicated that bmPGES could be involved in reproduction of B. mori. Therefore, this study provides insights into the physiological role of bmPGES and PGE2 in silkworms.


Assuntos
Óvulo/crescimento & desenvolvimento , Prostaglandina-E Sintases/fisiologia , Animais , Bombyx , Córion , Dinoprostona/deficiência , Dinoprostona/fisiologia , Edição de Genes , Reprodução
4.
Vet Immunol Immunopathol ; 192: 33-40, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29042013

RESUMO

Inhibition of prostaglandin E2 (PGE2) production effectively limits inflammation in horses, however nonspecific prostaglandin blockade via cyclooxygenase (COX) inhibition elicits deleterious gastrointestinal side effects in equine patients. Thus, more selective PGE2 targeting therapeutics are needed to treat inflammatory disease in horses. One potential target is microsomal prostaglandin E-synthase-1 (mPGES-1), which is the terminal enzyme downstream of COX-2 in the inducible PGE2 synthesis cascade. This enzyme has yet to be studied in equine leukocytes, which play a pivotal role in equine inflammatory disease. The objective of this study was to determine if mPGES-1 is a PGE2-selective anti-inflammatory target in equine leukocytes. To evaluate this objective, leukocyte-rich plasma (LRP) was isolated from equine whole blood collected via jugular venipuncture of six healthy adult horses of mixed breeds and genders. LRP was primed with granulocyte-monocyte colony-stimulating factor (GM-CSF) and stimulated with lipopolysaccharide (LPS) in the presence or absence of an mPGES-1 inhibitor (MF63), a COX-2 inhibitor (NS-398), or a nonselective COX inhibitor (indomethacin). Following treatment, mPGES-1 and COX-2 mRNA and protein levels were measured via qPCR and western blot, respectively, and PGE2, thromboxane (TXA2) and prostacyclin (PGI2) levels were measured in cellular supernatants via ELISA. This study revealed that LPS significantly increased mPGES-1 mRNA, but not protein levels in equine LRP as measured by qPCR and western blot, respectively. In contrast, COX-2 mRNA and protein were coordinately induced by LPS. Importantly, treatment of LPS-stimulated leukocytes with indomethacin and NS-398 significantly reduced extracellular concentrations of multiple prostanoids (PGE2, TXA2 and PGI2), while the mPGES-1 inhibitor MF63 selectively inhibited PGE2 production only. mPGES-1 inhibition also preserved higher basal levels of PGE2 production when compared to either COX inhibitor, which might be beneficial in a clinical setting. In conclusion, this work identifies mPGES-1 as a key regulator of PGE2 production and a PGE2-selective target in equine leukocytes. This study demonstrates that mPGES-1 is a potentially safer and effective therapeutic target for treatment of equine inflammatory disease when compared to traditional non-steroidal anti-inflammatory drugs.


Assuntos
Dinoprostona/antagonistas & inibidores , Inflamação/veterinária , Prostaglandina-E Sintases/antagonistas & inibidores , Animais , Western Blotting/veterinária , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática/veterinária , Cavalos , Inflamação/metabolismo , Inflamação/fisiopatologia , Leucócitos/metabolismo , Microssomos/enzimologia , Prostaglandina-E Sintases/metabolismo , Prostaglandina-E Sintases/fisiologia , Reação em Cadeia da Polimerase em Tempo Real/veterinária
5.
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
6.
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
7.
Circulation ; 134(4): 328-38, 2016 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-27440004

RESUMO

BACKGROUND: Inhibitors of cyclooxygenase-2 alleviate pain and reduce fever and inflammation by suppressing the biosynthesis of prostacyclin (PGI2) and prostaglandin E2. However, suppression of these prostaglandins, particularly PGI2, by cyclooxygenase-2 inhibition or deletion of its I prostanoid receptor also predisposes to accelerated atherogenesis and thrombosis in mice. By contrast, deletion of microsomal prostaglandin E synthase 1 (mPGES-1) confers analgesia, attenuates atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2, but increasing biosynthesis of PGI2. METHODS: To address the cardioprotective contribution of PGI2, we generated mice lacking the I prostanoid receptor together with mPges-1 on a hyperlipidemic background (low-density lipoprotein receptor knockouts). RESULTS: mPges-1 depletion modestly increased thrombogenesis, but this response was markedly further augmented by coincident deletion of the I prostanoid receptor (n=10-18). By contrast, deletion of the I prostanoid receptor had no effect on the attenuation of atherogenesis by mPGES-1 deletion in the low-density lipoprotein receptor knockout mice (n=17-21). CONCLUSIONS: Although suppression of prostaglandin E2 accounts for the protective effect of mPGES-1 deletion in atherosclerosis, augmentation of PGI2 is the dominant contributor to its favorable thrombogenic profile. The divergent effects on these prostaglandins suggest that inhibitors of mPGES-1 may be less likely to cause cardiovascular adverse effects than nonsteroidal anti-inflammatory drugs specific for inhibition of cyclooxygenase-2.


Assuntos
Aterosclerose/enzimologia , Epoprostenol/fisiologia , Hiperlipidemias/genética , Prostaglandina-E Sintases/deficiência , Receptores de Prostaglandina/deficiência , Animais , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Aterosclerose/genética , Artéria Carótida Primitiva/efeitos da radiação , Estenose das Carótidas/etiologia , Hiperlipidemias/enzimologia , Lasers/efeitos adversos , Camundongos , Camundongos Knockout , Microssomos/enzimologia , Polimorfismo de Nucleotídeo Único , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/fisiologia , Receptores de Epoprostenol , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/fisiologia
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