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1.
Molecules ; 27(19)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36234768

RESUMO

Over the last two decades, there has been an increasing awareness of the role of eicosanoids in the development and progression of several types of cancer, including breast, prostate, lung, and colorectal cancers. Several processes involved in cancer development, such as cell growth, migration, and angiogenesis, are regulated by the arachidonic acid derivative thromboxane A2 (TXA2). Higher levels of circulating TXA2 are observed in patients with multiple cancers, and this is accompanied by overexpression of TXA2 synthase (TBXAS1, TXA2S) and/or TXA2 receptors (TBXA2R, TP). Overexpression of TXA2S or TP in tumor cells is generally associated with poor prognosis, reduced survival, and metastatic disease. However, the role of TXA2 signaling in the stroma during oncogenesis has been underappreciated. TXA2 signaling regulates the tumor microenvironment by modulating angiogenic potential, tumor ECM stiffness, and host immune response. Moreover, the by-products of TXA2S are highly mutagenic and oncogenic, adding to the overall phenotype where TXA2 synthesis promotes tumor formation at various levels. The stability of synthetic enzymes and receptors in this pathway in most cancers (with few mutations reported) suggests that TXA2 signaling is a viable target for adjunct therapy in various tumors to reduce immune evasion, primary tumor growth, and metastasis.


Assuntos
Neoplasias , Tromboxano-A Sintase , Ácido Araquidônico , Eicosanoides , Humanos , Masculino , Neoplasias/genética , Receptores de Tromboxanos , Tromboxano A2 , Tromboxano-A Sintase/genética , Tromboxano-A Sintase/metabolismo , Tromboxanos , Microambiente Tumoral
2.
Life Sci ; 286: 120073, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34688694

RESUMO

AIMS: Thromboxane (TxA2) is synthesized from arachidonic acid (AA) via thromboxane synthase (TxS) enzyme and induces vasoconstriction via TP receptor. Our aim is to compare the effects of aspirin, TxS inhibitor and TP receptor antagonist on vascular reactivity of bypass grafts (saphenous vein and internal mammary artery). MAIN METHODS: Using isolated organ bath, saphenous vein and internal mammary artery preparations were incubated with TP receptor antagonist, TxS inhibitor, aspirin, IP or EP4 receptor antagonist. Then prostaglandin (PG)E2, PGF2α, phenylephrine and AA were administered in concentration-dependent manner. The expression of prostanoid receptor and PGI2 synthase (PGIS) enzyme was determined by Western Blot. KEY FINDINGS: TP receptor antagonist inhibited the contraction induced by PGE2, PGF2α, and AA but not that induced by phenylephrine in both types of vessels. Aspirin increased phenylephrine-induced contraction only in internal mammary artery and decreased AA-induced contraction in saphenous vein. TxS inhibitor decreased both PGE2 and AA-induced contraction in both types of vessels. This decrease was reversed by co-incubation of TxS inhibitor and IP/EP4 receptor antagonists. The expressions of EP3 receptor and PGIS enzyme were greater in internal mammary artery compared to saphenous vein while IP and TP receptors expressed at similar levels. SIGNIFICANCE: TP receptor antagonist and TxS inhibitor are more effective to reduce contraction induced by different spasmogens in comparison to aspirin. Our results suggest that TP receptor antagonist and TxS inhibitor might have an advantage over aspirin due to their preventive effect on increased vascular reactivity observed in post-operative period of coronary artery bypass grafting.


Assuntos
Artéria Torácica Interna/efeitos dos fármacos , Veia Safena/efeitos dos fármacos , Ácido Araquidônico/metabolismo , Aspirina/farmacologia , Benzofuranos/farmacologia , Carbazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Artéria Torácica Interna/metabolismo , Músculo Liso Vascular/metabolismo , Fenilefrina/farmacologia , Receptores de Prostaglandina/metabolismo , Receptores de Tromboxanos/antagonistas & inibidores , Receptores de Tromboxanos/efeitos dos fármacos , Receptores de Tromboxanos/metabolismo , Veia Safena/metabolismo , Sulfonamidas/farmacologia , Tromboxano A2/farmacologia , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxano-A Sintase/efeitos dos fármacos , Tromboxano-A Sintase/metabolismo , Tromboxanos/antagonistas & inibidores , Tromboxanos/metabolismo , Vasoconstrição/efeitos dos fármacos
3.
Dev Comp Immunol ; 120: 104069, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33737116

RESUMO

We report on a new insect prostanoid in a lepidopteran insect, Spodoptera exigua. Thromboxane B2 (TXB2) was detected by LC-MS/MS in extracts of larval epidermis, midgut, fat body and hemocytes, with highest amounts in hemocytes (about 300 ng/g tissue with substantial variation). Thromboxane A2 (TXA2) is an unstable intermediate that is non-enzymatically hydrolyzed into the stable TXB2. In S. exigua, both thromboxanes mediate at least two cellular immune responses to bacterial infection, hemocyte-spreading behavior and nodule formation. At the molecular level, a TXA2 synthase (SeTXAS) was identified from a group of 139 S. exigua cytochrome P450 monooxygenases. SeTXAS was highly similar to mammalian TXAS genes and is expressed in all developmental stages and four tested larval tissues. Immune challenge significantly enhanced SeTXAS expression, especially in hemocytes. RNA interference (RNAi) injections using gene-specific double stranded RNA led to reduced SeTXAS expression and suppressed the cellular immune responses, which were rescued following TXA2 or TXB2 injections. Unlike other PGs, TXA2 or TXB2 did not influence oocyte development in adult females. We infer that thromboxanes are present in insect tissues, where they mediate innate immune responses.


Assuntos
Atividade Bactericida do Sangue , Hemócitos/imunologia , Prostaglandinas/metabolismo , Spodoptera/imunologia , Tromboxanos/metabolismo , Animais , Escherichia coli/imunologia , Feminino , Hemócitos/metabolismo , Proteínas de Insetos/metabolismo , Larva , Oócitos/crescimento & desenvolvimento , Spodoptera/enzimologia , Spodoptera/microbiologia , Tromboxano-A Sintase/metabolismo
4.
Cell Biol Int ; 45(6): 1175-1182, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33527589

RESUMO

The current article aims to summarize all possible spectrum of protein-protein interactions for thromboxane A synthase (CYP5A1) and prostacyclin synthase (CYP8A1). These enzymes metabolize the same substrate (prostaglandin H2 ) and can participate in cardiovascular, inflammatory, immune processes, and apoptosis modulation, as well as significantly influence the risk of cancers. Binary protein-protein and multiprotein complexes are of great importance in enzyme-regulating and signal-transduction pathways. However, protein partners of CYP5A1 and CYP8A1 are not yet fully identified, although both synthases are considered as prospective drug targets. At least 36 novel protein partners of CYP5A1 and CYP8A1 were revealed from different tissue types using an approach based on affinity isolation and mass spectrometry. Enrichment analysis showed that these proteins have different molecular functions: folding (refolding), unfolded protein and chaperon binding, protein transport (export/import), posttranslational modification, protein domain-specific binding, antioxidant activity, and glutathione homeostasis. A significant part of them, belonging to molecular chaperones, were common partners for CYP5A1 and CYP8A1, while other proteins were unique with the tissue-dependent distribution. New aspects of CYP5A1 and CYP8A1 interactomics and hetero-complex formation with different protein partners, including cytochrome P450s are discussed.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Tromboxano-A Sintase/metabolismo , Humanos , Ligantes , Complexos Multiproteicos , Ligação Proteica
5.
Vascul Pharmacol ; 137: 106827, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33346090

RESUMO

The present study investigates the potential of ozagrel, a thromboxane A2 (TXA2) synthase inhibitor, in bilateral common carotid artery occlusion (BCCAo) induced vascular dementia (VaD). Wistar rats were subjected to BCCAo procedure under anesthesia to induce VaD. Morris water maze (MWM) test was employed on 7th day post-surgery to determine learning and memory. Endothelial dysfunction was assessed in isolated aorta by observing endothelial dependent vasorelaxation and levels of serum nitrite. A battery of biochemical and histopathological estimations was performed. Expression analysis of inflammatory cytokines TNF-α and IL-6 was carried out by RT-PCR. BCCAo produced significant impairment in endothelium dependent vasorelaxation and decrease in serum nitrite levels indicating endothelial dysfunction along with poor performance on MWM represents impairment of learning and memory. There was a significant rise in brain oxidative stress level (indicated by increase in brain thiobarbituric acid reactive species and decrease in reduced glutathione levels); increase in brain acetylcholinesterase activity; brain myeloperoxidase activity; brain TNF-α & IL-6 levels, brain TNF-α & IL-6 mRNA expression and brain neutrophil infiltration (as marker of inflammation) were also observed. Treatment of ozagrel (10 & 20 mg/kg, p. o.)/donepezil (0. 5 mg/kg, i.p., serving as standard) ameliorated BCCAo induced endothelial dysfunction; memory deficits; biochemical and histopathological changes in a significant manner. It may be concluded that ozagrel markedly improved endothelial dysfunction; learning and memory; biochemical and histopathological alteration associated with BCCAo induced VaD and that TXA2 can be considered as an important therapeutic target for the treatment of VaD.


Assuntos
Encéfalo/efeitos dos fármacos , Estenose das Carótidas/complicações , Demência Vascular/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Mediadores da Inflamação/metabolismo , Metacrilatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Tromboxano-A Sintase/antagonistas & inibidores , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Artéria Carótida Primitiva/cirurgia , Demência Vascular/enzimologia , Demência Vascular/etiologia , Demência Vascular/fisiopatologia , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Feminino , Ligadura , Masculino , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Ratos Wistar , Tromboxano-A Sintase/metabolismo
6.
Pflugers Arch ; 471(11-12): 1505-1517, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31736003

RESUMO

Advanced glycation end products (AGEs) play a pivotal role in vascular functions under various pathophysiological conditions. Although uridine diphosphate (UDP) is an important extracellular nucleotide, the relationship between AGEs and UDP regarding their effect on vascular functions remains unclear. Therefore, we investigated the effects of AGE-bovine serum albumin (AGE-BSA) on UDP-mediated responses in rat thoracic aorta and carotid arteries. In rat thoracic aorta, UDP-induced relaxation was observed and this relaxation was similar between control (1.0 v/v% PBS) and AGE-BSA-treated (0.1 mg/mL for 60 min) groups. In contrast, contraction but not relaxation was obtained following UDP application to carotid arteries with and without endothelia; contraction was greater in the AGE-BSA-treated group than in the control group. The difference in UDP-induced contraction between the two groups was not abolished by the use of a nitric oxide synthase (NOS) inhibitor, whereas it was abolished by the use of cyclooxygenase (COX), thromboxane synthase (TXS), and thromboxane-prostanoid (TP) receptor antagonist. Further, the difference in UDP-induced contraction was not abolished by the use of a cPLA2 inhibitor, whereas it was abolished by the use of an iPLA2 inhibitor. UDP increased TXA2 release in both groups, and its level was similar in both groups. Moreover, the release of PGE2, PGF2α, and PGI2 was similar among the groups. Under NOS inhibition, TP receptor agonist-induced contraction increased in the AGE-BSA-treated group (vs. control group). In conclusion, the increase in UDP-induced carotid arterial contraction by AGE-BSA can be attributed to an increase in the COX/TXS/TP receptor pathway, particularly, TP receptor signaling.


Assuntos
Artérias Carótidas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores de Tromboxanos/metabolismo , Tromboxano-A Sintase/metabolismo , Difosfato de Uridina/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Artérias Carótidas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
7.
J Cell Mol Med ; 23(12): 8343-8354, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31628732

RESUMO

Uncontrollable bleeding is still a worldwide killer. In this study, we aimed to investigate a novel approach to exhibit effective haemostatic properties, which could possibly save lives in various bleeding emergencies. According to the structure-based enzymatic design, we have engineered a novel single-chain hybrid enzyme complex (SCHEC), COX-1-10aa-TXAS. We linked the C-terminus of cyclooxygenase-1 (COX-1) to the N-terminus of the thromboxane A2 (TXA2 ) synthase (TXAS), through a 10-amino acid residue linker. This recombinant COX-1-10aa-TXAS can effectively pass COX-1-derived intermediate prostaglandin (PG) H2 (PGH2 ) to the active site of TXAS, resulting in an effective chain reaction property to produce the haemostatic prostanoid, TXA2 , rapidly. Advantageously, COX-1-10aa-TXAS constrains the production of other pro-bleeding prostanoids, such as prostacyclin (PGI2 ) and prostaglandin E2 (PGE2 ), through reducing the common substrate, PGH2 being passed to synthases which produce aforementioned prostanoids. Therefore, based on these multiple properties, this novel COX-1-10aa-TXAS indicated a powerful anti-bleeding ability, which could be used to treat a variety of bleeding situations and could even be useful for bleeding prone situations, including nonsteroidal anti-inflammatory drugs (NSAIDs)-resulted TXA2 -deficient and PGI2 -mediated bleeding disorders. This novel SCHEC has a great potential to be developed into a biological haemostatic agent to treat severe haemorrhage emergencies, which will prevent the complications of blood loss and save lives.


Assuntos
Aminoácidos/metabolismo , Ciclo-Oxigenase 1/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Tromboxano-A Sintase/metabolismo , Aminoácidos/genética , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/genética , Dinoprostona/metabolismo , Epoprostenol/metabolismo , Células HEK293 , Hemorragia/prevenção & controle , Hemostáticos/metabolismo , Hemostáticos/farmacologia , Humanos , Camundongos Transgênicos , Agregação Plaquetária/efeitos dos fármacos , Prostaglandina H2/metabolismo , Proteínas Recombinantes de Fusão/genética , Tromboxano A2/metabolismo , Tromboxano-A Sintase/genética
8.
Sci Rep ; 9(1): 13621, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541129

RESUMO

Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.


Assuntos
Arginina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Malária Cerebral/patologia , Animais , Arginina/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/patologia , Suplementos Nutricionais , Feminino , Malária Cerebral/metabolismo , Metacrilatos/metabolismo , Metacrilatos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmodium berghei/efeitos dos fármacos , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxano-A Sintase/metabolismo , Tromboxanos/antagonistas & inibidores , Tromboxanos/metabolismo , Vasoconstrição/efeitos dos fármacos
9.
Food Chem Toxicol ; 133: 110799, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31493463

RESUMO

Aluminum (Al) is toxic for humans and animals. Here, we have tested the potential for Egg White Hydrolysate (EWH) to protect against cardiovascular changes in rats exposed to both high and low dietary levels of Al. Indeed, EWH has been previously shown to improve cardio metabolic dysfunctions induced by chronic exposure to heavy metals. Male Wistar rats received orally: Group 1) Low aluminum level (AlCl3 at a dose of 8.3 mg/kg b.w. during 60 days) with or without EWH treatment (1 g/kg/day); Group 2) High aluminum level (AlCl3 at a dose of 100 mg/kg b.w. during 42 days) with or without EWH treatment. After Al treatment, rats co-treated with EWH did not show vascular dysfunction or increased blood pressure as was observed in non EWH-cotreated animals. Indeed, co-treatment with EWH prevented the following effects observed in both aorta and mesenteric arteries: the increased vascular responses to phenylephrine (Phe), the decreased ACh-induced relaxation, the reduction on endothelial modulation of vasoconstrictor responses and the nitric oxide bioavailability, as well as the increased reactive oxygen species production from NAD(P)H oxidase. Altogether, our results suggest that EWH could be used as a protective agent against the harmful vascular effects after long term exposure to Al.


Assuntos
Antioxidantes/farmacologia , Proteínas do Ovo/farmacologia , Clara de Ovo/química , Hidrolisados de Proteína/farmacologia , Doenças Vasculares/prevenção & controle , Alumínio , Animais , Antioxidantes/química , Ciclo-Oxigenase 2/metabolismo , Proteínas do Ovo/química , Endotélio Vascular/efeitos dos fármacos , Hidrólise , Masculino , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Tromboxano-A Sintase/metabolismo , Doenças Vasculares/induzido quimicamente , Vasoconstrição/efeitos dos fármacos
10.
Cell Microbiol ; 21(6): e13025, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30866138

RESUMO

Oxylipins, or oxygenated lipids, are universal signalling molecules across all kingdoms of life. These molecules, either produced by microbial pathogens or their mammalian host, regulate inflammation during microbial infection. In this review, we summarise current literature on the biosynthesis pathways of microbial oxylipins and their biological activity towards mammalian cells. Collectively, these studies have illustrated how microbial pathogens can modulate immune rsponse and disease outcome via oxylipin-mediated mechanisms.


Assuntos
Infecções Bacterianas/microbiologia , Inflamação/microbiologia , Micoses/microbiologia , Oxilipinas/metabolismo , Infecções por Protozoários/parasitologia , Animais , Bactérias/enzimologia , Bactérias/metabolismo , Infecções Bacterianas/imunologia , Eicosanoides/biossíntese , Eicosanoides/química , Eicosanoides/metabolismo , Epóxido Hidrolases/metabolismo , Fungos/enzimologia , Fungos/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Lipoxigenases/metabolismo , Oxilipinas/química , Oxilipinas/imunologia , Fosfolipases/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Tromboxano-A Sintase/metabolismo , Trypanosomatina/enzimologia , Trypanosomatina/metabolismo
11.
Hypertens Res ; 42(4): 450-458, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30542084

RESUMO

We examined the potential contributions of oxidative stress and thromboxane A2 (TXA2) to the development of regional heterogeneity in hypertensive glomerular injury using stroke-prone spontaneously hypertensive rats (SHRSP), an animal model of human essential hypertension. We also examined the effect of antioxidant treatment on the regional expression of thromboxane synthase (TXAS) mRNA using a microdissection method. Increases in the glomerular expression of TXAS mRNA were observed in the SHRSP at 15 weeks of age compared with those in the age-matched normotensive control Wistar-Kyoto (WKY) rats: 2.4-fold and 3.1-fold in the superficial and juxtamedullary glomeruli, respectively (P < 0.05). The heme oxygenase-1 mRNA expression was markedly increased (greater than eightfold, P < 0.05) in both the superficial and juxtamedullary glomeruli in the SHRSP compared with the expression in the WKY rats. In contrast to our expectations, the treatment of SHRSP with tempol (a superoxide dismutase mimetic) significantly (P < 0.05) increased the TXAS mRNA expression in the superficial glomeruli and did not improve the histological injury or albuminuria, which were both aggravated. Moreover, ozagrel (a TXAS inhibitor) had a suppressive effect on the TXAS mRNA expression and significantly (P < 0.05) improved the histological injury. These results indicated that although TXA2 and oxidative stress are linked to each other, TXA2 rather than oxidative stress may be a better therapeutic target to improve hypertensive glomerular injury.


Assuntos
Hipertensão/metabolismo , Glomérulos Renais/metabolismo , Estresse Oxidativo/fisiologia , Tromboxano A2/metabolismo , Tromboxano-A Sintase/metabolismo , Animais , Pressão Sanguínea , Heme Oxigenase-1/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
12.
Int J Mol Sci ; 19(10)2018 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-30274381

RESUMO

While arterial reflow after a stroke represents an important challenge for better outcomes, it is also very important that sudden recanalization does not produce local oxidative and nitrogen species, deleterious for the brain and more particularly the immature brain. Our objective was to determine whether a supply in prostaglandin (Pg) E1 (Alprostadil), via its action on arterial pressure, might progressively improve cerebral reperfusion in a neonatal stroke model. Arterial blood flow was measured using ultrasonography. Rate-limiting and Pg terminal synthesizing enzymes were evaluated using reverse-transcriptase polymerase chain reaction. Our data suggests that a supply in PgE1 might delay and improve the ipsilateral reperfusion by decreasing thromboxane A synthase-1 gene, the density of reactive astrocytes and lesion volume.


Assuntos
Alprostadil/uso terapêutico , Circulação Colateral/efeitos dos fármacos , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Alprostadil/farmacologia , Animais , Animais Recém-Nascidos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/enzimologia , Isquemia Encefálica/genética , Isquemia Encefálica/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Ratos Wistar , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/enzimologia , Tromboxano-A Sintase/genética , Tromboxano-A Sintase/metabolismo
13.
Thromb Haemost ; 118(11): 1982-1996, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30300909

RESUMO

OBJECTIVE: Activation of thromboxane A2 synthase (TXAS)/thromboxane A2 (TXA2)/thromboxane prostanoid (TP) receptor leads to arterial constriction, platelet aggregation and vascular injury. We attempted to characterize the microvascular dysfunction in ischaemia/reperfusion injury using genetically modified TXAS-/-, TP-/- and TXAS-/-TP-/- mice. APPROACH AND RESULTS: The cardiac micro-circulation and electrocardiograms were evaluated from B6, TXAS-/-, TP-/- and TXAS-/-TP-/- mice in response to intravenous saline, endothelin-1, U46619 (a TXA2 agonist) and myocardial ischaemia/reperfusion injury. Cardiac function was investigated with myocardial permeability, the troponin I concentration and the infarct size. Myocardial TXAS, TP, endothelial nitric oxide (NO) synthase (eNOS), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOx4), 4-hydroxynonenal, interleukin (IL)-1ß, cell apoptosis, coronary effluent thromboxane B2 (TXB2) and superoxide anions (O2 -) and NO concentrations were measured. Mice mesenteric reactivity in response to various drugs was assessed by wire myography. In vivo fluorescent platelet adhesiveness to the mesenteric arterial endothelium after FeCl3 stimulation was examined. In B6 mice, ischaemia/reperfusion significantly increased levels of ST-segment elevation, myocardial TXAS, TP, NOx4, IL-1ß, apoptosis, coronary endothelin-1, TXB2, O2 - release and the infarct size, with concomitant decreases in eNOS, NO concentrations and cardiac micro-circulation. These effects were remarkably depressed in TXAS-/-, TP-/- and TXAS-/-TP-/- mice. Aspirin treatment or depletion of the TXAS, TP or TXAS/TP gene significantly attenuated the exaggerated vascular reactivity by vasoconstrictors and vasodilators and efficiently reduced platelet adhesion to the mesenteric endothelium under FeCl3 stimulation. CONCLUSION: Inhibiting TXAS/TXA2/TP signalling confers microvascular protection against oxidative injury in both cardiac and mesenteric arteries.


Assuntos
Microvasos/metabolismo , Miocárdio/patologia , Receptores de Tromboxanos/metabolismo , Traumatismo por Reperfusão/metabolismo , Tromboxano-A Sintase/metabolismo , Animais , Permeabilidade Capilar , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/patologia , Miocárdio/metabolismo , Miografia , Estresse Oxidativo , Receptores de Tromboxanos/genética , Tromboxano A2/metabolismo , Tromboxano-A Sintase/genética , Troponina I/metabolismo
14.
Cancer Metastasis Rev ; 37(2-3): 439-454, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30112590

RESUMO

Platelets can serve as "first responders" in cancer and metastasis. This is partly due to bioactive lipid metabolism that drives both platelet and cancer biology. The two primary eicosanoid metabolites that maintain platelet rapid response homeostasis are prostacyclin made by endothelial cells that inhibits platelet function, which is counterbalanced by thromboxane produced by platelets during activation, aggregation, and platelet recruitment. Both of these arachidonic acid metabolites are inherently unstable due to their chemical structure. Tumor cells by contrast predominantly make more chemically stable prostaglandin E2, which is the primary bioactive lipid associated with inflammation and oncogenesis. Pharmacological, clinical, and epidemiologic studies demonstrate that non-steroidal anti-inflammatory drugs (NSAIDs), which target cyclooxygenases, can help prevent cancer. Much of the molecular and biological impact of these drugs is generally accepted in the field. Cyclooxygenases catalyze the rate-limiting production of substrate used by all synthase molecules, including those that produce prostaglandins along with prostacyclin and thromboxane. Additional eicosanoid metabolites include lipoxygenases, leukotrienes, and resolvins that can also influence platelets, inflammation, and carcinogenesis. Our knowledge base and technology are now progressing toward identifying newer molecular and cellular interactions that are leading to revealing additional targets. This review endeavors to summarize new developments in the field.


Assuntos
Plaquetas/metabolismo , Metabolismo dos Lipídeos , Neoplasias/etiologia , Neoplasias/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores , Plaquetas/efeitos dos fármacos , Epoprostenol/metabolismo , Glucose/metabolismo , Humanos , Imunomodulação , Inflamação/complicações , Inflamação/etiologia , Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoxigenase/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Oxigenases de Função Mista/metabolismo , Neoplasias/patologia , Neoplasias/prevenção & controle , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/metabolismo , Receptores de Prostaglandina/metabolismo , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxano-A Sintase/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-30039765

RESUMO

Atherothrombosis-related diseases are one of the world's leading causes of mortality, and thus the search for new therapeutic approaches in this area remains a very urgent task. Modern pharmacogenomic technologies make it possible to obtain valuable data on disease pathogenesis and optimal therapeutic approaches. One promising research direction is the study of the thromboxane A2 - thromboxane A synthase - thromboxane A2 receptor axis. This review summarizes the recent evidence and suggests that systematic works in this area are creating new and promising opportunities in the treatment of patients with cardiovascular diseases.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Inibidores Enzimáticos/uso terapêutico , Terapia de Alvo Molecular , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxano-A Sintase/metabolismo , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Humanos , Terapia de Alvo Molecular/métodos , Testes Farmacogenômicos , Agregação Plaquetária/efeitos dos fármacos , Polimorfismo Genético , Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tromboxano A2/metabolismo , Tromboxano-A Sintase/genética
17.
J Cell Mol Med ; 21(8): 1584-1592, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28244682

RESUMO

Extracellular histones are mediators of inflammation, tissue injury and organ dysfunction. Interactions between circulating histones and vascular endothelial cells are key events in histone-mediated pathologies. Our aim was to investigate the implication of extracellular histones in the production of the major vasoactive compounds released by human endothelial cells (HUVECs), prostanoids and nitric oxide (NO). HUVEC exposed to increasing concentrations of histones (0.001 to 100 µg/ml) for 4 hrs induced prostacyclin (PGI2) production in a dose-dependent manner and decreased thromboxane A2 (TXA2) release at 100 µg/ml. Extracellular histones raised cyclooxygenase-2 (COX-2) and prostacyclin synthase (PGIS) mRNA and protein expression, decreased COX-1 mRNA levels and did not change thromboxane A2 synthase (TXAS) expression. Moreover, extracellular histones decreased both, eNOS expression and NO production in HUVEC. The impaired NO production was related to COX-2 activity and superoxide production since was reversed after celecoxib (10 µmol/l) and tempol (100 µmol/l) treatments, respectively. In conclusion, our findings suggest that extracellular histones stimulate the release of endothelial-dependent mediators through an up-regulation in COX-2-PGIS-PGI2 pathway which involves a COX-2-dependent superoxide production that decreases the activity of eNOS and the NO production. These effects may contribute to the endothelial cell dysfunction observed in histone-mediated pathologies.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Epoprostenol/agonistas , Histonas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Tromboxano A2/antagonistas & inibidores , Celecoxib/farmacologia , Óxidos N-Cíclicos/farmacologia , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Epoprostenol/biossíntese , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/genética , Cultura Primária de Células , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Marcadores de Spin , Superóxidos/antagonistas & inibidores , Superóxidos/metabolismo , Tromboxano A2/biossíntese , Tromboxano-A Sintase/genética , Tromboxano-A Sintase/metabolismo
18.
J Stroke Cerebrovasc Dis ; 25(12): 2828-2837, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27567296

RESUMO

BACKGROUND AND PURPOSE: Ozagrel sodium (ozagrel), a thromboxane A2 synthesis inhibitor, is used for ischemic stroke patients in several countries, despite a lack of strict evidence of its benefits. We investigated whether ozagrel was beneficial for patients with atherothrombotic stroke or lacunar infarction. METHODS: This was a retrospective observational study using the Diagnosis Procedure Combination database in Japan. We identified patients with atherothrombotic stroke or lacunar infarction who were admitted to 781 hospitals from July 1, 2010 to March 31, 2012. Propensity score-matched analyses were performed separately for patients with atherothrombotic stroke and those with lacunar infarction, which balanced differences in baseline characteristics between patients who received ozagrel (ozagrel group) and those who did not (control group) in each stroke subtype. The modified Rankin Scale scores at discharge and occurrence of hemorrhagic complications after admission were compared between the ozagrel and control groups. RESULTS: After the propensity score matching, 2726 pairs of patients with atherothrombotic stroke and 1612 pairs of patients with lacunar infarction were analyzed. Ordinal logistic regression analyses showed that ozagrel use was not significantly associated with modified Rankin Scale score at discharge in patients with atherothrombotic stroke (odds ratio: .99; 95% confidence interval: .88-1.11) or in those with lacunar infarction (odds ratio: 1.00; 95% confidence interval: .87-1.16). The occurrence of hemorrhagic complications did not differ significantly between the ozagrel and control groups. CONCLUSION: The present study suggested that ozagrel was safe to use but did not improve functional outcomes in patients with atherothrombotic or lacunar infarction.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Metacrilatos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Tromboxano-A Sintase/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Distribuição de Qui-Quadrado , Avaliação da Deficiência , Inibidores Enzimáticos/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Modelos Logísticos , Masculino , Análise por Pareamento , Metacrilatos/efeitos adversos , Pessoa de Meia-Idade , Alta do Paciente , Pontuação de Propensão , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral Lacunar/diagnóstico , Acidente Vascular Cerebral Lacunar/tratamento farmacológico , Acidente Vascular Cerebral Lacunar/etiologia , Acidente Vascular Cerebral Lacunar/fisiopatologia , Tromboxano-A Sintase/metabolismo , Resultado do Tratamento
19.
Chem Biodivers ; 13(10): 1307-1315, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27449560

RESUMO

Isoepoxypteryxin is the major coumarin of a Japanese medicinal plant Angelica shikokiana. This research was designed to study the effect of structural changes through fungal biotransformation on the reported biological activities of isoepoxypteryxin. Among the tested microorganisms, only Cordyceps sinensis had enzymes that could catalyze the ester hydrolysis and the reductive cleavage of the epoxide ring of isoepoxypteryxin, separately, to give two more polar metabolites (+)-cis-khellactone (P1) and a new coumarin derivative (+)-cis-3'-[(2-methyl-3-hydroxybutanoyl)oxy]-4'-acetoxy-3',4'-dihydroseselin (P2), respectively. The polar metabolite P2 showed stronger cytotoxicity and higher selectivity than isoepoxypteryxin. On the molecular level, P2 showed more in vitro inhibition of both tubulin polymerization and histone deacetylase 8 (HDAC8). Similarly, P2 showed more neuroprotection against amyloid beta fragment 1 - 42 (Aß1 - 42 )-induced neurotoxicity in human neuroblastoma cells (SH-SY5Y) and exhibited more inhibition of the in vitro aggregation of Aß1 - 42 . Both metabolites showed stronger antiplatelet aggregation by increased inhibition of thromboxane-A2 synthase (TXS) activity and thromboxane-A2 (TXA2) production. This study is the first to describe the improved cytotoxic, neuroprotective, and antiplatelet aggregation activities of isoepoxypteryxin through its biotransformation by C. sinensis.


Assuntos
Angelica/química , Cordyceps/enzimologia , Cordyceps/metabolismo , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fármacos Neuroprotetores/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Angelica/metabolismo , Animais , Biocatálise , Biotransformação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Histona Desacetilases/metabolismo , Humanos , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/metabolismo , Polimerização/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Tromboxano A2/metabolismo , Tromboxano-A Sintase/antagonistas & inibidores , Tromboxano-A Sintase/metabolismo , Tubulina (Proteína)/metabolismo
20.
J Surg Res ; 204(1): 153-63, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27451882

RESUMO

BACKGROUND: Thromboxane A synthase (TXAS) is the enzyme that converts the arachidonic acid derivative prostaglandin H2 to thromboxane A2 (TXA2). TXA2 induces platelet aggregation, vasoconstriction, and proliferation. TXAS and TXA2 receptors or thromboxane prostanoid (TP) receptors are elevated in numerous cardiovascular and inflammatory diseases. Platelets contain numerous angiogenesis stimulating factors. However, the involvement of TXAS on recovery from an ischemic condition is not well understood. We hypothesized that the TXAS-TXA2-TP receptor axis would induce blood flow recovery by platelet activation. MATERIAL AND METHODS: The model of hindlimb ischemia was made by the right femoral artery ligation. The blood flow was estimated by laser Doppler images. Angiogenesis was estimated by the plasma level of the vascular endothelial growth factor and the stromal cell-derived factor-1 and by immunofluorescence analysis against CD31 and P-selectin glycoprotein ligand-1 (PSGL-1). RESULTS: In wild-type mice, blood flow recovery was enhanced by treatment with murine TXAS-overexpressing fibroblasts (C57-mTXAS) compared with empty vector- (EV) treated fibroblasts (C57-EV). Compared with C57-EV-treated mice, activated platelets (P-selectin(+) platelets) and plasma levels of vascular endothelial growth factor and stromal cell-derived factor-1 were increased in C57-mTXAS-treated mice. The enhanced-blood flow recovery by C57-mTXAS treatment was suppressed in the TP knockout mice (TP(-/-)). The expression of PSGL-1 in endothelial cells around the ischemic area was enhanced by C57-mTXAS treatment in wild-type but not in TP(-/-). CONCLUSIONS: These results indicated that local administration of C57-mTXAS-induced angiogenesis by activated platelets that bind to PSGL-1 on ischemic endothelial cells.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Membro Posterior/irrigação sanguínea , Isquemia/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Ativação Plaquetária/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Tromboxano-A Sintase/uso terapêutico , Animais , Biomarcadores/metabolismo , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacologia , Linhagem Celular , Artéria Femoral/cirurgia , Fibroblastos/enzimologia , Fibroblastos/transplante , Membro Posterior/diagnóstico por imagem , Membro Posterior/metabolismo , Isquemia/diagnóstico por imagem , Isquemia/metabolismo , Fluxometria por Laser-Doppler , Ligadura , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica/fisiologia , Ativação Plaquetária/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Tromboxano A2/metabolismo , Tromboxano-A Sintase/metabolismo , Tromboxano-A Sintase/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
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