Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.245
Filtrar
1.
Cell Prolif ; 54(2): e12964, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33314534

RESUMO

OBJECTIVES: 20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid catalysed by cytochrome P450 enzymes and plays an important role in cell death and proliferation. We hypothesized that 20-HETE synthesis inhibition may have protective effects in traumatic brain injury (TBI) and investigated possible underlying molecular mechanisms. MATERIALS AND METHODS: Neurologic deficits, and lesion volume, reactive oxygen species (ROS) levels and cell death as assessed using immunofluorescence staining, transmission electron microscopy and Western blotting were used to determine post-TBI effects of HET0016, an inhibitor of 20-HETE synthesis, and their underlying mechanisms. RESULTS: The level of 20-HETE was found to be increased significantly after TBI in mice. 20-HETE synthesis inhibition reduced neuronal apoptosis, ROS production and damage to mitochondrial structures after TBI. Mechanistically, HET0016 decreased the Drp1 level and increased the expression of Mfn1 and Mfn2 after TBI, indicating a reversal of the abnormal post-TBI mitochondrial dynamics. HET0016 also promoted the restoration of SIRT1 and PGC-1α in vivo, and a SIRT1 activator (SRT1720) reversed the downregulation of SIRT1 and PGC-1α and the abnormal mitochondrial dynamics induced by 20-HETE in vitro. Furthermore, plasma 20-HETE levels were found to be higher in TBI patients with unfavourable neurological outcomes and were correlated with the GOS score. CONCLUSIONS: The inhibition of 20-HETE synthesis represents a novel strategy to mitigate TBI-induced mitochondrial dysfunction and neuronal apoptosis by regulating the SIRT1/PGC-1α pathway.


Assuntos
Amidinas/farmacologia , Apoptose/efeitos dos fármacos , Lesões Encefálicas Traumáticas/patologia , Ácidos Hidroxieicosatetraenoicos/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Lesões Encefálicas Traumáticas/veterinária , Dinaminas/metabolismo , Feminino , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Ácidos Hidroxieicosatetraenoicos/farmacologia , Modelos Logísticos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/citologia , Neurônios/metabolismo , Neurônios/ultraestrutura , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/química , Sirtuína 1/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(25): 14376-14385, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32513718

RESUMO

Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1-PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1-PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1-PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.


Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Asma/imunologia , Autofagia/imunologia , Células Epiteliais/patologia , Ferroptose/imunologia , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Adulto , Animais , Asma/diagnóstico , Asma/patologia , Líquido da Lavagem Broncoalveolar/citologia , Linhagem Celular , Sobrevivência Celular/imunologia , Células Epiteliais/imunologia , Feminino , Técnicas de Inativação de Genes , Humanos , Ácidos Hidroxieicosatetraenoicos/imunologia , Ácidos Hidroxieicosatetraenoicos/metabolismo , Interleucina-13/imunologia , Interleucina-13/metabolismo , Masculino , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Simulação de Dinâmica Molecular , Proteína de Ligação a Fosfatidiletanolamina/genética , Fosfatidiletanolaminas/imunologia , Fosfatidiletanolaminas/metabolismo , Cultura Primária de Células , Ligação Proteica/imunologia , Índice de Gravidade de Doença
3.
Nat Chem Biol ; 16(7): 783-790, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32393899

RESUMO

Leukotrienes (LT) are lipid mediators of the inflammatory response that are linked to asthma and atherosclerosis. LT biosynthesis is initiated by 5-lipoxygenase (5-LOX) with the assistance of the substrate-binding 5-LOX-activating protein at the nuclear membrane. Here, we contrast the structural and functional consequences of the binding of two natural product inhibitors of 5-LOX. The redox-type inhibitor nordihydroguaiaretic acid (NDGA) is lodged in the 5-LOX active site, now fully exposed by disordering of the helix that caps it in the apo-enzyme. In contrast, the allosteric inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA) from frankincense wedges between the membrane-binding and catalytic domains of 5-LOX, some 30 Å from the catalytic iron. While enzyme inhibition by NDGA is robust, AKBA promotes a shift in the regiospecificity, evident in human embryonic kidney 293 cells and in primary immune cells expressing 5-LOX. Our results suggest a new approach to isoform-specific 5-LOX inhibitor development through exploitation of an allosteric site in 5-LOX.


Assuntos
Araquidonato 5-Lipoxigenase/química , Produtos Biológicos/química , Inibidores de Lipoxigenase/química , Masoprocol/química , Triterpenos/química , Sítio Alostérico , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Produtos Biológicos/metabolismo , Domínio Catalítico , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Humanos , Ácidos Hidroxieicosatetraenoicos/química , Ácidos Hidroxieicosatetraenoicos/metabolismo , Leucotrieno B4/química , Leucotrieno B4/metabolismo , Inibidores de Lipoxigenase/metabolismo , Masoprocol/metabolismo , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidade por Substrato , Triterpenos/metabolismo
4.
Nephrol Dial Transplant ; 35(2): 303-312, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137494

RESUMO

BACKGROUND: The clinical relevance of arachidonic acid (AA) metabolites in chronic kidney disease (CKD) progression is poorly understood. We aimed to compare the concentrations of 85 enzymatic pathway products of AA metabolism in patients with CKD who progressed to end-stage kidney disease (ESKD) versus patients who did not in a subcohort of Chronic Renal Insufficiency Cohort (CRIC) and to estimate the risk of CKD progression and major cardiovascular events by levels of AA metabolites and their link to enzymatic metabolic pathways. METHODS: A total 123 patients in the CRIC study who progressed to ESKD were frequency matched with 177 nonprogressors and serum eicosanoids were quantified by mass spectrometry. We applied serum collected at patients' Year 1 visit and outcome of progression to ESKD was ascertained over the next 10 years. We used logistic regression models for risk estimation. RESULTS: Baseline 15-hydroxyeicosatetraenoate (HETE) and 20-HETE levels were significantly elevated in progressors (false discovery rate Q ≤ 0.026). The median 20-HETE level was 7.6 pmol/mL [interquartile range (IQR) 4.2-14.5] in progressors and 5.4 pmol/mL (IQR 2.8-9.4) in nonprogressors (P < 0.001). In an adjusted model, only 20-HETE independently predicted CKD progression. Each 1 standard deviation increase in 20-HETE was independently associated with 1.45-fold higher odds of progression (95% confidence interval 1.07-1.95; P = 0.017). Principal components of lipoxygenase (LOX) and cytochrome P450 (CYP450) pathways were independently associated with CKD progression. CONCLUSIONS: We found higher odds of CKD progression associated with higher 20-HETE, LOX and CYP450 metabolic pathways. These alterations precede CKD progression and may serve as targets for interventions aimed at halting progression.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Falência Renal Crônica/diagnóstico , Lipoxigenase/metabolismo , Insuficiência Renal Crônica/complicações , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade
5.
Nanotoxicology ; 14(4): 453-467, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31775543

RESUMO

Bioactive, oxygenated metabolites of polyunsaturated fatty acids (PUFAs) are important indicators of inflammation and oxidative stress but almost nothing is known about their interactions with nanomaterials (NMs). To investigate the effects of nano-sized materials (n-TiO2, n-ZnO, n-Ag) and their bulk-sized or ionic (b-TiO2, b-ZnO, i-Ag) counterpart, we studied the status of oxidative stress and PUFA metabolism in THP-1 cells at low-toxic concentrations (<15% cytotoxicity) 6 h or 24 h after the particle exposures by LC/MS and microarray. N-Ag had a significant and sustained impact on cellular antioxidant defense, seen as incremental synthesis and accumulation of glutathione (GSH) in the cell, and reduction of superoxide dismutase (SOD) activity. The cellular particle doses were largely dependent on exposure duration and particle dissolution, and active transporter mechanisms controlled the concentration of Zn in cytosol. Even at these sub-toxic concentrations, n-Ag was able to induce statistically significant elevation in the 5-HETE: arachidonic acid ratio at 24 h, which suggests association to oxidative stress and induction of pro-inflammatory responses. This was supported by the enhanced gene expression of chemotaxis-related genes. Overall, THP-1 cells internalized all tested particles, but only n-Ag led to low level of oxidative stress through ROS production and antioxidant balance disruption. N-Ag stimulated arachidonic acid oxidation to form 5-HETE which further magnified the inflammatory responses by enhancing the production of mitochondrial superoxide and leukocyte chemokines. Since the sustained n-Ag uptake was detected, the effects may last long and function as a trigger for the low-grade inflammation playing role in the chronic inflammatory diseases.


Assuntos
Ácidos Hidroxieicosatetraenoicos/metabolismo , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Prata/toxicidade , Titânio/toxicidade , Óxido de Zinco/toxicidade , Antioxidantes/metabolismo , Glutationa/metabolismo , Humanos , Inflamação , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/imunologia , Células THP-1
6.
Oncol Rep ; 43(1): 147-158, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31789401

RESUMO

Acyl­CoA synthetase long­chain family member 4 (ACSL4) is a member of the long chain family of acyl­CoA synthetase proteins, which have recently been shown to serve an important role in ferroptosis. Previous studies have suggested that ferroptosis is involved in the occurrence of glioma; however, the role of ACSL4 in glioma remains unknown. In the present study, a reduction of ferroptosis in human glioma tissues and glioma cells was observed. Subsequently, it was demonstrated that the expression of ACSL4 was also downregulated in human glioma tissues and cells. A ferroptosis inhibitor and inducer were used to investigate the effects of ferroptosis on viability. The results showed that promoting ferroptosis inhibited the proliferation of glioma cells, and that the use of inducers had the reverse effect. Therefore, it was hypothesized that the reduction in ACSL4 expression may have been involved in ferroptosis and proliferation in glioma. Overexpression of ACSL4 decreased expression of glutathione peroxidase 4 and increased the levels of ferroptotic markers, including 5­hydroxyeicosatetraenoic (HETE), 12­HETE and 15­HETE. Additionally, ACSL4 overexpression resulted in an increase in lactate dehydrogenase release and a reduction in cell viability. The opposite results were observed when ACSL4 was silenced. These findings suggest that ACSL4 regulates ferroptosis and proliferation of glioma cells. To further investigate the mechanism underlying ACSL4­mediated regulation of proliferation in glioma cells, cells were treated with small interfering (si)­ACSL4 and sorafenib, a ferroptosis inducer. sorafenib attenuated the ability of siRNA­mediated silencing of ACSL4, thus improving cell viability. These results demonstrate that ACSL4 protects glioma cells and exerts anti­proliferative effects by activating a ferroptosis pathway and highlight the pivotal role of ferroptosis regulation by ACSL4 in its protective effects on glioma. Therefore, ACSL4 may serve as a novel therapeutic target for the treatment of glioma.


Assuntos
Neoplasias Encefálicas/metabolismo , Coenzima A Ligases/metabolismo , Regulação para Baixo , Ferroptose , Glioma/metabolismo , Adulto , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Coenzima A Ligases/antagonistas & inibidores , Regulação para Baixo/efeitos dos fármacos , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ferroptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/patologia , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Interferente Pequeno/farmacologia , Sorafenibe/farmacologia
7.
Mol Med Rep ; 21(1): 393-404, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746392

RESUMO

Cardiovascular disease is the predominant complication and leading cause of mortality in patients with chronic kidney disease (CKD). Previous studies have revealed that uremic toxins, including indoxyl sulfate (IS), participate in cardiac hypertrophy. As a heme­thiolate monooxygenase, cytochrome P450 family 1 subfamily B member 1 (CYP1B1) is able to metabolize arachidonic acid into hydroxyeicosatetraenoic acids, which are thought to serve a central function in the pathophysiology of the cardiovascular system. However, whether CYP1B1 is involved in cardiac hypertrophy induced by uremic toxins remains unknown. The present study revealed that the expression of the CYP1B1 gene was significantly (P<0.05, CKD or IS vs. control) upregulated by CKD serum or IS at the transcriptional and translational level. Furthermore, IS treatment resulted in the nuclear translocation of aryl hydrocarbon receptor (AhR), an endogenous ligand of IS. Binding of AhR in the promoter region of CYP1B1 was confirmed using a chromatin immunoprecipitation assay in the cardiomyoblast H9c2 cell line. In addition, knockdown of AhR or CYP1B1 reversed the production of cardiac hypertrophy markers. The in vivo injection of a CYP1B1 inhibitor significantly (P<0.05, Inhibitor vs. control) attenuated cardiac hypertrophy in mice. The data from the present study clearly demonstrated that CYP1B1 was involved in cardiac hypertrophy induced by uremic toxins.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomegalia/genética , Citocromo P-450 CYP1B1/genética , Ácidos Hidroxieicosatetraenoicos/genética , Receptores de Hidrocarboneto Arílico/genética , Animais , Ácido Araquidônico/genética , Ácido Araquidônico/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Linhagem Celular , Citocromo P-450 CYP1B1/antagonistas & inibidores , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Indicã/toxicidade , Camundongos , Ratos , Ativação Transcricional/efeitos dos fármacos
8.
Artigo em Inglês | MEDLINE | ID: mdl-31760076

RESUMO

PURPOSE: Recent studies have shown that 20-hydroxyeicosatetraenoic acid (20-HETE) is a key molecule in sustaining androgen-mediated prostate cancer cell survival. Thus, the aim of this study was to determine whether 20-HETE can affect the metastatic potential of androgen-insensitive prostate cancer cells, and the implication of the newly described 20-HETE receptor, GPR75, in mediating these effects. METHODS: The expression of GPR75, protein phosphorylation, actin polymerization and protein distribution were assessed by western blot and/or fluorescence microscopy. Additionally, in vitro assays including epithelial-mesenchymal transition (EMT), metalloproteinase-2 (MMP-2) activity, scratch wound healing, transwell invasion and soft agar colony formation were used to evaluate the effects of 20-HETE agonists/antagonists or GPR75 gene silencing on the aggressive features of PC-3 cells. RESULTS: 20-HETE (0.1 nM) promoted the acquisition of a mesenchymal phenotype by increasing EMT, the release of MMP-2, cell migration and invasion, actin stress fiber formation and anchorage-independent growth. Also, 20-HETE augmented the expression of HIC-5, the phosphorylation of EGFR, NF-κB, AKT and p-38 and the intracellular redistribution of p-AKT and PKCα. These effects were impaired by GPR75 antagonism and/or silencing. Accordingly, the inhibition of 20-HETE formation with N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) elicited the opposite effects. CONCLUSIONS: The present results show for the first time the involvement of the 20-HETE-GPR75 receptor in the activation of intracellular signaling known to be stimulated in cell malignant transformations leading to the differentiation of PC-3 cells towards a more aggressive phenotype. Targeting the 20-HETE/GPR75 pathway is a promising and novel approach to interfere with prostate tumor cell malignant progression.


Assuntos
Ácidos Hidroxieicosatetraenoicos/metabolismo , Neoplasias da Próstata/patologia , Receptores Acoplados a Proteínas-G/metabolismo , Amidinas/farmacologia , Androgênios/metabolismo , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Ácidos Hidroxieicosatetraenoicos/agonistas , Ácidos Hidroxieicosatetraenoicos/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas com Domínio LIM/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais/efeitos dos fármacos
9.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514409

RESUMO

Hypertension is the most common modifiable risk factor for stroke, and understanding the underlying mechanisms of hypertension and hypertension-related stroke is crucial. 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid (20-HETE), which plays an important role in vasoconstriction, autoregulation, endothelial dysfunction, angiogenesis, inflammation, and blood-brain barrier integrity, has been linked to hypertension and stroke. 20-HETE can promote hypertension by potentiating the vascular response to vasoconstrictors; it also can reduce blood pressure by inhibition of sodium transport in the kidney. The production of 20-HETE is elevated after the onset of both ischemic and hemorrhagic strokes; on the other hand, subjects with genetic variants in CYP4F2 and CYP4A11 that reduce 20-HETE production are more susceptible to stroke. This review summarizes recent genetic variants in CYP4F2, and CYP4A11 influencing 20-HETE production and discusses the role of 20-HETE in hypertension and the susceptibility to the onset, progression, and prognosis of ischemic and hemorrhagic strokes.


Assuntos
Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipertensão/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Progressão da Doença , Humanos , Modelos Biológicos , Polimorfismo Genético
10.
Curr Hypertens Rep ; 21(10): 79, 2019 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-31494743

RESUMO

PURPOSE OF REVIEW: To examine outstanding issues in the relationship of alcohol to hypertension. These include whether the increase in BP with alcohol is causally related, the nature of the relationship in women, the contribution of alcohol-related increases in BP to cardiovascular disease and the aetiology of alcohol-related hypertension. RECENT FINDINGS: Intervention studies and Mendelian randomisation analyses confirm the alcohol-BP relationship is causal. The concept that low-level alcohol intake reduces BP in women is increasingly unsustainable. Alcohol-related hypertension is in the causal pathway between alcohol use and increased risk for several cardiovascular outcomes. The aetiology of alcohol-related hypertension is multifactorial with recent data highlighting the effects of alcohol on the vasoconstrictor 20-HETE and oxidative stress. The high prevalence of both alcohol use and hypertension mandates a careful alcohol history in every patient with elevated BP. Early intervention for excessive alcohol use offers the promise of lower levels of BP and reduced risk of adverse cardiovascular outcomes.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Etanol/farmacologia , Hipertensão/fisiopatologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/etiologia , Transtornos Relacionados ao Uso de Álcool/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/fisiopatologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Etanol/efeitos adversos , Feminino , Humanos , Ácidos Hidroxieicosatetraenoicos/efeitos adversos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipertensão/etiologia , Hipertensão/metabolismo , Masculino , Análise da Randomização Mendeliana , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Estresse Oxidativo/fisiologia , Fatores de Risco , Fatores Sexuais
11.
Biochemistry ; 58(38): 3990-4002, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31469551

RESUMO

Aspirin and Celebrex are well-known time-dependent inhibitors of the cyclooxygenases (COX). Molecular dynamics simulations suggest that Arg-513 and Leu-531 contribute to the structural mechanisms of COX inhibition. We used mutagenesis and functional analyses to characterize how substitutions at these positions influence time-dependent inhibition by aspirin and Celebrex. We show that substitutions of Leu-531 with asparagine and phenylalanine significantly attenuate time-dependent inhibition of COX-2 by these drugs. The introduction of side chain bulk, rigidity, and charge would disrupt the formation of the initial noncovalent complex, in the case of aspirin, and the "high-affinity" binding state, in the case of Celebrex. Substitution of Arg-513 with histidine (the equivalent residue in COX-1) resulted in a 2-fold potentiation of aspirin inhibition, in support of the hypothesis that the presence of histidine in COX-1 lowers the activation barrier associated with the formation of the initial noncovalent enzyme-inhibitor complex. As a corollary, we previously hypothesized that the flexibility associated with Leu-531 contributes to the binding of arachidonic acid (AA) to acetylated COX-2 to generate 15R-hydroxyeicosatetraenoic acid (15R-HETE). We determined the X-ray crystal structure of AA bound to Co3+-protoporphyrin IX-reconstituted V349I murine COX-2 (muCOX-2). V349I muCOX-2 was utilized as a surrogate to trap AA in a conformation leading to 15R-HETE. AA binds in a C-shaped pose, facilitated by the rotation of the Leu-531 side chain. Ile-349 is positioned to sterically shield antarafacial oxygen addition at carbon-15 in a manner similar to that proposed for the acetylated Ser-530 side chain.


Assuntos
Aspirina/farmacologia , Celecoxib/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Animais , Ácido Araquidônico/química , Ácido Araquidônico/metabolismo , Arginina/genética , Arginina/metabolismo , Cristalografia por Raios X , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/isolamento & purificação , Ensaios Enzimáticos , Histidina , Ácidos Hidroxieicosatetraenoicos/química , Ácidos Hidroxieicosatetraenoicos/metabolismo , Leucina/genética , Leucina/metabolismo , Mutagênese Sítio-Dirigida , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Células Sf9 , Estereoisomerismo , Especificidade por Substrato , Fatores de Tempo
12.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1126-1127: 121748, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437772

RESUMO

The kidneys play an important role in the long-term regulation of blood pressure by control of salt and water balance in the body through various systems including the endocannabinoid system. The endocannabinoid system consists of the two major cannabinoid receptor agonists, anandamide (AEA) and 2-arachidonylglycerol (2-AG), their hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), and the cannabinoid receptors, CB1 and CB2. AEA can be converted into 12- and 15(S)-hydroperoxyeicosatetraenoic acid ethanolamides by 12-LOX and 15-LOX, respectively and can form epoxyeicosatrienoic acid- (EET-EAs) (5,6-, 8,9-, 11,12-, 14,15-) and hydroxyeicosatetraenoic acid- (HETE) ethanolamides. Furthermore, the EET-EAs produce a secondary metabolism by microsomal epoxide hydrolase to form the corresponding dihydroxyeicosatetraenoic acid-EAs (DiHETE-EA). Reference material was not available for DiHETE-EA. These metabolites were synthesized by incubation of the corresponding EET-EAs with mouse liver cytosol containing epoxide hydrolases. Presented is a solid phase extraction and high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for the extraction and quantitation of AEA, 2-AG, their metabolites, oleoylethanolamide (OEA), and palmitoylethanolamide (PEA), and the in vivo formation of the DiHETE-EAs in kidney after a single intravenous bolus administration of 20 mg/kg of anandamide in C57BL/6 J and FAAH KO mice.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Etanolaminas , Ácidos Hidroxieicosatetraenoicos , Rim , Espectrometria de Massas em Tandem/métodos , Animais , Endocanabinoides/metabolismo , Etanolaminas/análise , Etanolaminas/metabolismo , Ácidos Hidroxieicosatetraenoicos/análise , Ácidos Hidroxieicosatetraenoicos/metabolismo , Rim/química , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
Sci Rep ; 9(1): 12033, 2019 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-31427689

RESUMO

Oxylipids are potent lipid mediators associated with inflammation-induced colon carcinomas and colon tumor survival. Therefore, oxylipid profiles may be useful as novel biomarkers of colon polyp presence. The aim of this study was to investigate the relationship between plasma non-esterified oxylipids and the presence of colon polyps. A total of 123 Caucasian men, ages 48 to 65, were categorized into three groups: those with no polyps, those with one or more hyperplastic polyps, and those with one or more adenomas. Plasma non-esterified oxylipids were analyzed using solid phase extraction and quantified using a targeted HPLC tandem mass spectrometric analysis. Statistical analyses included Kruskal-Wallis one-way ANOVA with Dunn's test for multiple comparison and generalized linear models to adjust for confounding factors such as age, anthropometrics, and smoking status. In general, monohydroxy omega-6-derived oxylipids were significantly increased in those with polyps. Concentrations of 5-hydroxyeicosatetraenoic acid (HETE) and 11-HETE were significantly higher in those with hyperplastic polyps and adenomas compared to those with no polyps. Arachidonic acid-derived HETEs were significantly associated with colon polyp types, even after adjusting for age, smoking, and body mass index or waist circumference in regression models. Since many of these oxylipids are formed through oxygenation by lipoxygenases (i.e., 5-, 12-, and 15-HETE, and 15- hydroxyeicosatrienoic acid [HETrE]) or auto-oxidative reactions (i.e., 11-HETE), this may indicate that lipoxygenase activity and lipid peroxidation are increased in those with colon polyps. In addition, since oxylipids such as 5-, 12-, and 15-HETE are signaling molecules involved in inflammation regulation, these oxylipids may have important functions in inflammation-associated polyp presence. Future studies should be performed in a larger cohorts to investigate if these oxylipids are useful as potential biomarkers of colon polyps.


Assuntos
Ácido Araquidônico/efeitos adversos , Pólipos do Colo/epidemiologia , Pólipos do Colo/etiologia , Ácidos Hidroxieicosatetraenoicos/efeitos adversos , Fatores Etários , Idoso , Ácido Araquidônico/sangue , Ácido Araquidônico/metabolismo , Biomarcadores , Pólipos do Colo/diagnóstico , Estudos Transversais , Suscetibilidade a Doenças , Ácidos Graxos Ômega-3/sangue , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Ácidos Hidroxieicosatetraenoicos/metabolismo , Lipidômica , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
14.
Inflammopharmacology ; 27(5): 903-910, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359235

RESUMO

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammatory conditions such as arthritis. However, both arthritis and many NSAIDs increase cardiovascular (CV) risks. The dose-dependency of the elevated CV risks of NSAIDs has not been well-studied. We tested the hypothesis that low but still effective doses of these drugs are void of CV side effects. As the model drug, we chose diclofenac because of its known high CV toxicity, as markers of CV risks, we assessed concentrations of cytochrome P450-mediated metabolites of arachidonic acid (ArA), and we used adjuvant arthritis as an experimental model of arthritis. Following 7 daily doses (2.5-15 mg/kg), the effective dosage range of diclofenac was identified (> 5 mg/kg/day). While 7 consecutive days of low therapeutic doses did not alter the CYP-mediated ArA metabolism, the highest dose of 15 mg/kg/day caused imbalances in ArA metabolic profiles toward cardiotoxicity by increasing the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids. This is suggestive of dose-dependency of NSAID cardiotoxicity, and that low therapeutic doses may be void of CV side effects. Human studies are needed to examine the safety of low but effective doses of NSAIDs.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Artrite Experimental/tratamento farmacológico , Doenças Cardiovasculares/induzido quimicamente , Animais , Ácido Araquidônico/metabolismo , Artrite Experimental/metabolismo , Diclofenaco/administração & dosagem , Diclofenaco/efeitos adversos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Risco
15.
Acta Physiol (Oxf) ; 227(2): e13297, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077555

RESUMO

AIM: Imbalances in cytochrome P450 (CYP)-dependent eicosanoid formation may play a central role in ischemic acute kidney injury (AKI). We reported previously that inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) action ameliorated ischemia/reperfusion (I/R)-induced AKI in rats. Now we tested the hypothesis that enhancement of epoxyeicosatrienoic acid (EET) actions may counteract the detrimental effects of 20-HETE and prevent the initiation of AKI. METHODS: Male Lewis rats underwent right nephrectomy and ischemia was induced by 45 min clamping of the left renal pedicle followed by up to 48 h of reperfusion. Circulating CYP-eicosanoid profiles were compared in patients who underwent cardiac surgery with (n = 21) and without (n = 38) developing postoperative AKI. RESULTS: Ischemia induced an about eightfold increase of renal 20-HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15-EET analogue was administered by intrarenal infusion before ischemia. The EET analogue improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analogue improved PI3K- as well as mTORC2-dependent rephosphorylation of Akt, induced inactivation of GSK-3ß, reduced the development of tubular apoptosis and attenuated inflammatory cell infiltration. The EET analogue also significantly alleviated the I/R-induced drop in creatinine clearance. Patients developing postoperative AKI featured increased preoperative 20-HETE and 8,9-EET levels. CONCLUSIONS: Pharmacological interventions targeting the CYP-eicosanoid pathway could offer promising new options for AKI prevention. Individual differences in CYP-eicosanoid formation may contribute to the risk of developing AKI in clinical settings.


Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Lesão Renal Aguda/prevenção & controle , Ácidos Graxos/farmacologia , Ácidos Hidroxieicosatetraenoicos/sangue , Isquemia/etiologia , Ácido 8,11,14-Eicosatrienoico/administração & dosagem , Ácido 8,11,14-Eicosatrienoico/metabolismo , Lesão Renal Aguda/patologia , Animais , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ácidos Graxos/química , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Isquemia/patologia , Rim/metabolismo , Masculino , Complicações Pós-Operatórias , Ratos , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais
16.
J Biol Chem ; 294(26): 10146-10159, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31080170

RESUMO

Recently, oxidized phospholipid species have emerged as important signaling lipids in activated immune cells and platelets. The canonical pathway for the synthesis of oxidized phospholipids is through the release of arachidonic acid by cytosolic phospholipase A2α (cPLA2α) followed by its enzymatic oxidation, activation of the carboxylate anion by acyl-CoA synthetase(s), and re-esterification to the sn-2 position by sn-2 acyltransferase activity (i.e. the Lands cycle). However, recent studies have demonstrated the unanticipated significance of sn-1 hydrolysis of arachidonoyl-containing choline and ethanolamine glycerophospholipids by other phospholipases to generate the corresponding 2-arachidonoyl-lysolipids. Herein, we identified a pathway for oxidized phospholipid synthesis comprising sequential sn-1 hydrolysis by a phospholipase A1 (e.g. by patatin-like phospholipase domain-containing 8 (PNPLA8)), direct enzymatic oxidation of the resultant 2-arachidonoyl-lysophospholipids, and the esterification of oxidized 2-arachidonoyl-lysophospholipids by acyl-CoA-dependent sn-1 acyltransferase(s). To circumvent ambiguities associated with acyl migration or hydrolysis, we developed a synthesis for optically active (d- and l-enantiomers) nonhydrolyzable analogs of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC). sn-1 acyltransferase activity in murine liver microsomes stereospecifically and preferentially utilized the naturally occurring l-enantiomer of the ether analog of lysophosphatidylcholine. Next, we demonstrated the high selectivity of the sn-1 acyltransferase activity for saturated acyl-CoA species. Importantly, we established that 2-15-hydroxyeicosatetraenoic acid (HETE) ether-LPC sn-1 esterification is markedly activated by thrombin treatment of murine platelets to generate oxidized PC. Collectively, these findings demonstrate the enantiomeric specificity and saturated acyl-CoA selectivity of microsomal sn-1 acyltransferase(s) and reveal its participation in a previously uncharacterized pathway for the synthesis of oxidized phospholipids with cell-signaling properties.


Assuntos
Aciltransferases/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Lisofosfolipídeos/metabolismo , Fosfolipases/metabolismo , Fosfolipídeos/metabolismo , Acilação , Aciltransferases/genética , Animais , Plaquetas/metabolismo , Ácidos Hidroxieicosatetraenoicos/química , Lisofosfolipídeos/química , Camundongos , Microssomos Hepáticos/metabolismo , Oxirredução , Fosfolipídeos/química , Especificidade por Substrato
17.
Chem Biol Interact ; 307: 116-124, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063766

RESUMO

Naringenin is a flavanone compound found in citrus fruits. Recent researches showed that naringenin has many potentially pharmacological effects. However, the therapeutic effect and the potential mechanism of naringenin on diabetic nephropathy (DN) remain to be elucidated. DN model was established by a high-fat diet combined with streptozotocin (STZ), which was confirmed by the levels of fasting blood glucose (FBG, more than 11.1 mmol/L) and urinary albumin (10 times higher than the normal mice). After 5 weeks of STZ injection, the DN was developed in model mice. Then naringenin (25 or 75 mg/kg·d) were supplemented for 4 weeks. At the end of the experiment, the injury of the renal function and structure was deteriorated. Concomitantly, peroxisome proliferators-activated receptors (PPARs) protein expression was down-regulated, and CYP4A expression and 20-hydroxyeicosatetraenoic acid (20-HETE) level were reduced in DN mice. Naringenin administration improved the renal damage of DN mice, and up-regulated PPARs expression, increased CYP4A-20-HETE level. Consistent with the results of in vivo, glucose at 30 mmol/L (high glucose, HG) significantly induced cell proliferation and hypertrophy in NRK-52E cells, following the reductive PPARs protein expression and the downward CYP4A-20-HETE level. Naringenin (0.01, 0.1, 1 µmol/L) reversed these changes induced by HG in a dose-dependent manner. HET0016, a selective inhibitor of 20-HETE synthase, partially blocked the effects of naringenin. In conclusion, naringenin has a therapeutic effect on DN, which may be, at least partly, related to the activation of CYP4A-20-HETE and the up-regulation of PPARs.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Flavanonas/uso terapêutico , Ácidos Hidroxieicosatetraenoicos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP4A/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Dieta Hiperlipídica , Feminino , Flavanonas/farmacologia , Glucose/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos , Ratos , Estreptozocina/toxicidade , Regulação para Cima/efeitos dos fármacos
18.
Am J Physiol Heart Circ Physiol ; 316(6): H1468-H1479, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951365

RESUMO

20-Hydroxyeicosatetraenoic acid (20-HETE) was recently identified as a novel contributor of ischemia-induced neovascularization based on the key observation that pharmacological interferences of CYP4A/20-HETE decrease ischemic neovascularization. The objective of the present study is to examine whether the underlying cellular mechanisms involve endothelial progenitor cells (EPCs) and preexisting endothelial cells (ECs). We found that ischemia leads to a time-dependent increase of cyp4a12 expression and 20-HETE production, which are endothelial in origin, using immunofluorescent microscopy, Western blot analysis, and LC-MS/MS. This is accompanied by increases in the tissue stromal cell-derived factor-1α (SDF-1α) expressions as well as SDF-1α plasma levels, EPC mobilization from bone marrow, and subsequent homing to ischemic tissues. Pharmacological interferences of CYP4A/20-HETE with a 20-HETE synthesis inhibitor, dibromo-dodecenyl-methylsulfimide (DDMS), or a 20-HETE antagonist, N-(20-hydroxyeicosa-6(Z), 15(Z)-dienoyl) glycine (6, 15-20-HEDGE), significantly attenuated these increases. Importantly, we also determined that 20-HETE plays a novel role in maintaining EPC functions and increasing the expression of Oct4, Sox2, and Nanog, which are indicative of increased progenitor cell stemness. Flow cytometric analysis revealed that pharmacological interferences of CYP4A/20-HETE decrease the EPC population in culture, whereas 20-HETE increases the cultured EPC population. Furthermore, ischemia also markedly increased the proliferation, oxidative stress, and ICAM-1 expression in the preexisting EC in the hindlimb gracilis muscles. We found that these increases were markedly negated by DDMS and 6, 15-20-HEDGE. Taken together, CYP4A/20-HETE regulates ischemia-induced compensatory neovascularization via its combined actions on promoting EPC and local preexisting EC responses that are associated with increased neovascularization. NEW & NOTEWORTHY CYP4A/20-hydroxyeicosatetraenoic acid (20-HETE) was recently discovered as a novel contributor of ischemia-induced neovascularization. However, the underlying molecular and cellular mechanisms are completely unknown. Here, we show that CYP4A/20-HETE regulates the ischemic neovascularization process via its combined actions on both endothelial progenitor cells (EPCs) and preexisting endothelial cells. Moreover, this is the first study, to the best of our knowledge, that associates CYP4A/20-HETE with EPC differentiation and stemness.


Assuntos
Citocromo P-450 CYP4A/metabolismo , Células Endoteliais/enzimologia , Células Progenitoras Endoteliais/enzimologia , Ácidos Hidroxieicosatetraenoicos/metabolismo , Isquemia/enzimologia , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Animais , Células Cultivadas , Quimiocina CXCL12/metabolismo , Família 4 do Citocromo P450/metabolismo , Modelos Animais de Doenças , Membro Posterior , Humanos , Isquemia/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Proteína Homeobox Nanog/genética , Proteína Homeobox Nanog/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais , Fatores de Tempo
19.
PLoS One ; 14(3): e0214250, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921410

RESUMO

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.


Assuntos
Carbolinas/farmacologia , Epilepsia/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Doenças Mitocondriais/tratamento farmacológico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Ubiquinona/análogos & derivados , Araquidonato 15-Lipoxigenase/metabolismo , Linhagem Celular , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ubiquinona/farmacologia
20.
Chem Biol Interact ; 299: 140-150, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543782

RESUMO

Cytochrome P450 (P450) enzymes are superfamily of monooxygenases that hold the utmost diversity of substrate structures and catalytic reaction forms amongst all other enzymes. P450 enzymes metabolize arachidonic acid (AA) to a wide array of biologically active lipid mediators. P450-mediated AA metabolites have a significant role in normal physiological and pathophysiological conditions, hence they could be promising therapeutic targets in different disease states. P450 monooxygenases mediate the (ω-n)-hydroxylation reactions, which involve the introduction of a hydroxyl group to the carbon skeleton of AA, forming subterminal hydroxyeicosatetraenoic acids (HETEs). In the current review, we specified different P450 isozymes implicated in the formation of subterminal HETEs in varied tissues. In addition, we focused on the role of subterminal HETEs namely 19-HETE, 16-HETE, 17-HETE and 18-HETE in different organs, importantly the kidneys, heart, liver and brain. Furthermore, we highlighted their role in hypertension, acute coronary syndrome, diabetic retinopathy, non-alcoholic fatty liver disease, ischemic stroke as well as inflammatory diseases. Since each member of subterminal HETEs exist as R and S enantiomer, we addressed the issue of stereoselectivity related to the formation and differential effects of these enantiomers. In conclusion, elucidation of different roles of subterminal HETEs in normal and disease states leads to identification of novel therapeutic targets and development of new therapeutic modalities in different disease states.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipertensão/patologia , Animais , Ácido Araquidônico/metabolismo , Humanos , Hipertensão/metabolismo , Isoenzimas/metabolismo , Preparações Farmacêuticas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA