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Interactions between the upper ocean and air-ice-ocean fluxes in the Southern Ocean play a critical role in global climate by impacting the overturning circulation and oceanic heat and carbon uptake. Remote and challenging conditions have led to sparse observational coverage, while ongoing field programmes often fail to collect sufficient information in the right place or at the time-space scales required to constrain the variability occurring in the coupled ocean-atmosphere system. Only within the last 10 years have we been able to directly observe and assess the role of the fine-scale ocean and rapidly evolving atmospheric marine boundary layer on the upper limb of the Southern Ocean's overturning circulation. This review summarizes advances in mechanistic understanding, arising in part from observational programmes using autonomous platforms, of the fine-scale processes (1-100 km, hours-seasons) influencing the Southern Ocean mixed layer and its variability. We also review progress in observing the ocean interior connections and the coupled interactions between the ocean, atmosphere and cryosphere that moderate air-sea fluxes of heat and carbon. Most examples provided are for the ice-free Southern Ocean, while major challenges remain for observing the ice-covered ocean. We attempt to elucidate contemporary research gaps and ongoing/future efforts needed to address them. This article is part of a discussion meeting issue 'Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities'.
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The Gulf Stream front separates the North Atlantic subtropical and subpolar ocean gyres, water masses with distinct physical and biogeochemical properties. Exchange across the front is believed to be necessary to balance the freshwater budget of the subtropical gyre and to support the biological productivity of the region; however, the physical mechanisms responsible have been the subject of long-standing debate. Here, the evolution of a passive dye released within the north wall of the Gulf Stream provides direct observational evidence of enhanced mixing across the Gulf Stream front. Numerical simulations indicate that the observed rapid cross-frontal mixing occurs via shear dispersion, generated by frontal instabilities and episodic vertical mixing. This provides unique direct evidence for the role of submesoscale fronts in generating lateral mixing, a mechanism which has been hypothesized to be of general importance for setting the horizontal structure of the ocean mixed layer. Along the Gulf Stream front in the North Atlantic, these observations further suggest that shear dispersion at sharp fronts may provide a source of freshwater flux large enough to explain much of the freshwater deficit in the subtropical-mode water budget and a flux of nutrients comparable to other mechanisms believed to control primary productivity in the subtropical gyre.
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Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.
Assuntos
Síndrome Coronariana Aguda/economia , Síndrome Coronariana Aguda/terapia , Citocromo P-450 CYP2C19/genética , Custos de Medicamentos , Técnicas de Diagnóstico Molecular/economia , Intervenção Coronária Percutânea , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/economia , Inibidores da Agregação Plaquetária/uso terapêutico , Síndrome Coronariana Aguda/genética , Aspirina/economia , Aspirina/uso terapêutico , Clopidogrel/economia , Clopidogrel/uso terapêutico , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Terapia Antiplaquetária Dupla/economia , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Valor Preditivo dos Testes , Anos de Vida Ajustados por Qualidade de Vida , Ticagrelor/economia , Ticagrelor/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the frequency and clinical impact of switches in antiplatelet therapy following implementation of CYP2C19 genotyping after percutaneous coronary intervention (PCI). METHODS: The frequency of escalation (clopidogrel switched to prasugrel/ticagrelor) and de-escalation (prasugrel/ticagrelor switched to clopidogrel) was evaluated in 1063 PCI patients who underwent CYP2C19 genotyping. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and bleeding events over one year was evaluated. RESULTS: Antiplatelet therapy switches were common (19%), with escalation (101/115: 88%) and de-escalation (77/84: 92%) occurring predominantly in patients with and without a CYP2C19 nonfunctional allele, respectively. Nonfunctional allele carriers initiated and continued on clopidogrel had a significantly higher risk of experiencing either a MACCE or bleeding event compared with those escalated to prasugrel/ticagrelor (52 vs. 19 events/100 patient-years; adjusted hazard ratio [HR] 2.89 [1.44-6.13], p = 0.003). Patients without a nonfunctional allele de-escalated to clopidogrel had no difference in risk compared with those initiated and continued on prasugrel/ticagrelor (21 vs. 19 events/100 patient-years; adjusted HR 1.13 [0.51-2.34], p = 0.751). CONCLUSION: CYP2C19-guided escalation and de-escalation is common in a real-world setting. Continuation of clopidogrel in nonfunctional allele carriers is associated with adverse outcomes. De-escalation to clopidogrel in patients without a nonfunctional allele appears safe and warrants prospective study.
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Clopidogrel/administração & dosagem , Oclusão Coronária/terapia , Citocromo P-450 CYP2C19/genética , Inibidores da Agregação Plaquetária/administração & dosagem , Cloridrato de Prasugrel/administração & dosagem , Ticlopidina/administração & dosagem , Idoso , Clopidogrel/efeitos adversos , Oclusão Coronária/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Medicina de Precisão , Estudos Prospectivos , Ticlopidina/efeitos adversos , Resultado do TratamentoRESUMO
Current guidelines recommend dual antiplatelet therapy-a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y12 inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.
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Síndrome Coronariana Aguda/tratamento farmacológico , Citocromo P-450 CYP2C19/genética , Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Síndrome Coronariana Aguda/genética , Alelos , Biotransformação/genética , Ensaios Clínicos como Assunto , Clopidogrel/farmacocinética , Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/sangue , Citocromo P-450 CYP2C19/metabolismo , Genótipo , Humanos , Mutação com Perda de Função , Metanálise como Assunto , Seleção de Pacientes , Inibidores da Agregação Plaquetária/uso terapêutico , Guias de Prática Clínica como Assunto , Medicina de Precisão , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , RiscoRESUMO
OBJECTIVE: To evaluate the cost-effectiveness of multigene testing (CYP2C19, SLCO1B1, CYP2C9, VKORC1) compared with single-gene testing (CYP2C19) and standard of care (no genotyping) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) from Medicare's perspective. METHODS: A hybrid decision tree/Markov model was developed to simulate patients post-PCI for ACS requiring antiplatelet therapy (CYP2C19 to guide antiplatelet selection), statin therapy (SLCO1B1 to guide statin selection), and anticoagulant therapy in those that develop atrial fibrillation (CYP2C9/VKORC1 to guide warfarin dose) over 12 months, 24 months, and lifetime. The primary outcome was cost (2016 US dollar) per quality-adjusted life years (QALYs) gained. Costs and QALYs were discounted at 3% per year. Probabilistic sensitivity analysis (PSA) varied input parameters (event probabilities, prescription costs, event costs, health-state utilities) to estimate changes in the cost per QALY gained. RESULTS: Base-case-discounted results indicated that the cost per QALY gained was $59 876, $33 512, and $3780 at 12 months, 24 months, and lifetime, respectively, for multigene testing compared with standard of care. Single-gene testing was dominated by multigene testing at all time horizons. PSA-discounted results indicated that, at the $50 000/QALY gained willingness-to-pay threshold, multigene testing had the highest probability of cost-effectiveness in the majority of simulations at 24 months (61%) and over the lifetime (81%). CONCLUSIONS: On the basis of projected simulations, multigene testing for Medicare patients post-PCI for ACS has a higher probability of being cost-effective over 24 months and the lifetime compared with single-gene testing and standard of care and could help optimize medication prescribing to improve patient outcomes.
Assuntos
Síndrome Coronariana Aguda/economia , Síndrome Coronariana Aguda/terapia , Anticoagulantes/economia , Anticoagulantes/uso terapêutico , Custos de Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases/economia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Intervenção Coronária Percutânea/economia , Testes Farmacogenômicos/economia , Variantes Farmacogenômicos , Inibidores da Agregação Plaquetária/economia , Inibidores da Agregação Plaquetária/uso terapêutico , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Anticoagulantes/efeitos adversos , Análise Custo-Benefício , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C9/genética , Árvores de Decisões , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Cadeias de Markov , Medicare/economia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Inibidores da Agregação Plaquetária/efeitos adversos , Medicina de Precisão/economia , Valor Preditivo dos Testes , Anos de Vida Ajustados por Qualidade de Vida , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Vitamina K Epóxido Redutases/genéticaRESUMO
Our goal was to measure the association of CXCL5 and molecular phenotypes associated with coronary atherosclerosis severity in patients at least 65 years old. CXCL5 is classically defined as a proinflammatory chemokine, but its role in chronic inflammatory diseases, such as coronary atherosclerosis, is not well defined. We enrolled individuals who were at least 65 years old and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating CXCL5 levels were measured from plasma, and both DNA genotyping and mRNA expression levels in peripheral blood mononuclear cells were quantified via microarray gene chips. We observed a negative association of CXCL5 levels with CAD at an odds ratio (OR) of 0.46 (95% CI, 0.27-0.75). Controlling for covariates, including sex, statin use, hypertension, hyperlipidemia, obesity, self-reported race, smoking, and diabetes, the OR was not significantly affected [OR, 0.54 (95% CI, 0.31-0.96)], consistent with a protective role for CXCL5 in coronary atherosclerosis. We also identified 18 genomic regions with expression quantitative trait loci of genes correlated with both CAD severity and circulating CXCL5 levels. Our clinical findings are consistent with the emerging link between chemokines and atherosclerosis and suggest new therapeutic targets for CAD.
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Quimiocina CXCL5/sangue , Doença da Artéria Coronariana/sangue , Idoso , Quimiocina CXCL5/genética , Doença da Artéria Coronariana/genética , Feminino , Humanos , MasculinoRESUMO
Inhibition of soluble epoxide hydrolase (sEH, EPHX2) elicits potent cardiovascular protective effects in preclinical models of ischemic cardiovascular disease (CVD), and genetic polymorphisms in EPHX2 have been associated with developing ischemic CVD in humans. However, it remains unknown whether EPHX2 variants are associated with prognosis following an ischemic CVD event. We evaluated the association between EPHX2 p.Lys55Arg and p.Arg287Gln genotype with survival in 667 acute coronary syndrome (ACS) patients. No association with p.Arg287Gln genotype was observed (P = 0.598). Caucasian EPHX2 Arg55 carriers (Lys/Arg or Arg/Arg) had a significantly higher risk of 5-year mortality (adjusted hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.01-2.55, P = 0.045). In an independent population of 2712 ACS patients, this association was not replicated (adjusted HR 0.92, 95% CI 0.70-1.21, P = 0.559). In a secondary analysis, Caucasian homozygous Arg55 allele carriers (Arg/Arg) appeared to exhibit a higher risk of cardiovascular mortality (adjusted HR 2.60, 95% CI 1.09-6.17). These results demonstrate that EPHX2 p.Lys55Arg and p.Arg287Gln polymorphisms do not significantly modify survival after an ACS event. Investigation of other sEH metabolism biomarkers in ischemic CVD appears warranted.
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Síndrome Coronariana Aguda/genética , Substituição de Aminoácidos , Epóxido Hidrolases/genética , Polimorfismo de Nucleotídeo Único , Síndrome Coronariana Aguda/etnologia , Síndrome Coronariana Aguda/mortalidade , Negro ou Afro-Americano/genética , Idoso , Feminino , Frequência do Gene , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , População Branca/genéticaRESUMO
Cyclooxygenase-derived thromboxane (TxA2) and prostacyclin (PGI2) regulate atherogenesis in preclinical models. However, the relationship between TxA2 and PGI2 biosynthesis, vascular inflammation, and atherosclerotic cardiovascular disease (ASCVD) progression in humans remains unclear. The association between stable urine metabolites of thromboxane (TxA2-M) and prostacyclin (PGI2-M), circulating levels of cellular adhesion molecules (CAMs: E-selectin, P-selectin), chemokines and C-reactive protein, and the incidence of major adverse cardiovascular events (MACE) were evaluated in 120 patients with stable ASCVD on aspirin therapy. Urinary TxA2-M levels were significantly correlated with circulating P-selectin (r=0.319, p<0.001) and E-selectin (r=0.245, p=0.007) levels, and associated with higher risk of MACE (p=0.043). In contrast, PGI2-M levels were not significantly associated with CAM levels or MACE. These results provide insight into the contribution of TxA2 biosynthesis to ASCVD progression in humans, and suggest that patients with elevated TxA2-M levels may be predisposed to advanced platelet and endothelial activation and higher risk of adverse cardiovascular outcomes.
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Aterosclerose/diagnóstico , Aterosclerose/urina , Tromboxano B2/análogos & derivados , Determinação de Ponto Final , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/urina , Masculino , Pessoa de Meia-Idade , Prognóstico , Tromboxano B2/urinaRESUMO
Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.
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Ácido Araquidônico/metabolismo , Ácidos Araquidônicos/metabolismo , Doença da Artéria Coronariana/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ácido 8,11,14-Eicosatrienoico/sangue , Adulto , Idoso , Ácidos Araquidônicos/sangue , Biomarcadores/sangue , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Sistema Enzimático do Citocromo P-450/sangue , Feminino , Humanos , Ácidos Hidroxieicosatetraenoicos/sangue , Inflamação/sangue , Inflamação/metabolismo , Masculino , Metabolômica , Pessoa de Meia-IdadeRESUMO
Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Ácido 8,11,14-Eicosatrienoico/metabolismo , Adulto , Animais , Citocromo P-450 CYP2J2 , Dieta/efeitos adversos , Progressão da Doença , Epóxido Hidrolases/química , Epóxido Hidrolases/metabolismo , Feminino , Humanos , Hidrólise , Fígado/enzimologia , Masculino , Síndrome Metabólica/complicações , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , SolubilidadeRESUMO
Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.
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Eicosanoides/farmacologia , Células Endoteliais/metabolismo , Compostos de Epóxi/farmacologia , Neovascularização Fisiológica/fisiologia , Regeneração/fisiologia , Animais , Cromatografia Líquida , Eicosanoides/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Compostos de Epóxi/metabolismo , Olho/irrigação sanguínea , Imuno-Histoquímica , Rim/fisiologia , Fígado/fisiologia , Pulmão/fisiologia , Camundongos , Camundongos Transgênicos , Neovascularização Fisiológica/efeitos dos fármacos , Receptor TIE-2/genética , Regeneração/efeitos dos fármacos , Espectrometria de Massas em TandemRESUMO
Cytochrome P450 (CYP) 4A and 4F enzymes metabolize arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). Although CYP4A-derived 20-HETE is known to have prohypertensive and proangiogenic properties, the effects of CYP4F-derived metabolites are not well characterized. To investigate the role of CYP4F2 in vascular disease, we generated mice with endothelial expression of human CYP4F2 (Tie2-CYP4F2-Tr). LC/MS/MS analysis revealed 2-foldincreases in 20-HETE levels in tissues and endothelial cells (ECs), relative to wild-type (WT) controls. Tie2-CYP4F2-Tr ECs demonstrated increases in growth (267.1 ± 33.4 vs. 205.0 ± 13% at 48 h) and tube formation (7.7 ± 1.1 vs. 1.6 ± 0.5 tubes/field) that were 20-HETE dependent and associated with up-regulation of prooxidant NADPH oxidase and proangiogenic VEGF. Increases in VEGF and NADPH oxidase levels were abrogated by inhibitors of NADPH oxidase and MAPK, respectively, suggesting the possibility of crosstalk between pathways. Interestingly, IL-6 levels in Tie2-CYP4F2-Tr mice (18.6 ± 2.7 vs. 7.9 ± 2.7 pg/ml) were up-regulated via NADPH oxidase- and 20-HETE-dependent mechanisms. Although Tie2-CYP4F2-Tr aortas displayed increased vasoconstriction, vasorelaxation and blood pressure were unchanged. Our findings indicate that human CYP4F2 significantly increases 20-HETE production, CYP4F2-derived 20-HETE mediates EC proliferation and angiogenesis via VEGF- and NADPH oxidase-dependent manners, and the Tie2-CYP4F2-Tr mouse is a novel model for examining the pathophysiological effects of CYP4F2-derived 20-HETE in the vasculature.-Cheng, J., Edin, M. L., Hoopes, S. L., Li, H., Bradbury, J. A., Graves, J. P., DeGraff, L. M., Lih, F. B., Garcia, V., Shaik, J. S. B., Tomer, K. B., Flake, G. P., Falck, J. R., Lee, C. R., Poloyac, S. M., Schwartzman, M. L., Zeldin, D. C. Vascular characterization of mice with endothelial expression of cytochrome P450 4F2.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Células Endoteliais/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Animais , Pressão Sanguínea/genética , Células Cultivadas , Família 4 do Citocromo P450 , Citocinas/genética , Citocinas/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estresse Oxidativo/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Regulação para Cima/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Increased CYP epoxygenase activity and consequently up regulation of epoxyeicosatrienoic acids (EETs) levels provides protection against metabolic syndrome and cardiovascular diseases. Conversion of arachidonic acid epoxides to diols by soluble epoxide hydrolase (sEH) diminishes the beneficial cardiovascular properties of these epoxyeicosanoids. We therefore examined the possible biochemical consequences of sEH deletion on vascular responses in male and female mice. Through the use of the sEH KO mouse, we provide evidence of differences in the compensatory response in the balance between nitric oxide (NO), carbon monoxide (CO), EETs and the vasoconstrictor 20-HETE in male and female KO mice. Serum levels of adiponectin, TNFα, IL-1b and MCP1 and protein expression in vascular tissue of p-AMPK, p-AKT and p-eNOS were measured. Deletion of sEH caused a significant (p<0.05) decrease in body weight, and an increase in adiponectin, pAMPK and pAKT levels in female KO mice compared to male KO mice. Gene deletion resulted in a higher production of renal EETs in female KO compared to male KO mice and, concomitantly, we observed an increase in renal 20-HETEs levels and superoxide anion production only in male KO mice. sEH deletion increased p-AKT and p-eNOS protein expression but decreased p-AMPK levels in female KO mice. Increased levels of p-eNOS at Thr-495 were observed only in KO male mice. While p-eNOS at 1177 were not significantly different between male and female. Nitric oxide production was unaltered in male KO mice. These results provide evidence of gender differences in the preservation of vascular homeostasis in response to sEH deletion which involves regulation of phosphorylation of eNOS at the 495 site.
Assuntos
Vasos Sanguíneos/metabolismo , Epóxido Hidrolases/deficiência , Epóxido Hidrolases/genética , Técnicas de Inativação de Genes , Homeostase/genética , Caracteres Sexuais , Animais , Peso Corporal/genética , Citocinas/sangue , Eicosanoides/metabolismo , Epóxido Hidrolases/química , Feminino , Regulação Enzimológica da Expressão Gênica/genética , Ácidos Hidroxieicosatetraenoicos/metabolismo , Masculino , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/química , Óxido Nítrico Sintase Tipo III/metabolismo , Fosforilação/genética , Proteínas Proto-Oncogênicas c-akt/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina/metabolismo , Solubilidade , Superóxidos/metabolismo , Treonina/metabolismoRESUMO
Nanoparticles (NPs) are cleared by monocytes and macrophages. Chemokines CCL2 and CCL5 are key mediators for recruitment of these immune cells into tumors and tissues. The purpose of this study was to investigate effects of CCL2 and CCL5 on the pharmacokinetics (PKs) of NPs. Mice deficient in CCL2 or CCL5 demonstrated altered clearance and tissue distribution of polyethylene glycol tagged liposomal doxorubicin (PLD) compared to control mice. The PK studies using mice bearing SKOV3 ovarian cancer xenografts revealed that the presence of tumor cells and higher expression of chemokines were significantly associated with greater clearance of PLD compared to non-tumor bearing mice. Plasma exposure of encapsulated liposomal doxorubicin positively correlated with the total exposure of plasma CCL2 and CCL5 in patients with recurrent epithelial ovarian cancer treated with PLD. These data emphasize that the interplay between PLD and chemokines may have an important role in optimizing PLD therapy. FROM THE CLINICAL EDITOR: The use of nanoparticles as drug delivery carriers is gaining widespread acceptance in the clinical setting. However, the underlying pharmacokinetics of these novel drugs has not really been elucidated. In this interesting article, the authors carried out experiments using mice deficient in CCL2 or CCL5 to study the clearance of liposomal system. They showed the important role the immune system played and would enable better designs of future drug delivery systems.
Assuntos
Quimiocina CCL2/sangue , Quimiocina CCL5/sangue , Doxorrubicina/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Animais , Carcinoma Epitelial do Ovário , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Distribuição Tecidual/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cardiovascular disease, including acute myocardial infarction (AMI), is the leading cause of morbidity and mortality globally, despite well-established treatments. The discovery and development of novel therapeutics that prevent the progression of devastating consequences following AMI are thus important in reducing the global burden of this devastating disease. Scientific evidence for the protective effects of epoxyeicosatrienoic acids (EETs) in the cardiovascular system is rapidly emerging and suggests that promoting the effects of these cytochrome P450-derived epoxyeicosanoids is a potentially viable clinical therapeutic strategy. Through a translational lens, this review will provide insight into the potential clinical utility of this therapeutic strategy for AMI by 1) outlining the known cardioprotective effects of EETs and underlying mechanisms demonstrated in preclinical models of AMI with a particular focus on myocardial ischemia-reperfusion injury, 2) describing studies in human cohorts that demonstrate a relationship between EETs and associated pathways with coronary artery disease risk, and 3) discussing preclinical and clinical areas that require further investigation in order to increase the probability of successfully translating this rapidly emerging body of evidence into a clinically applicable therapeutic strategy for AMI.
Assuntos
Cardiotônicos/uso terapêutico , Eicosanoides/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Ensaios Clínicos como Assunto , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epóxido Hidrolases/genética , Epóxido Hidrolases/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Medicina de Precisão , Pesquisa Translacional BiomédicaRESUMO
Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences.
Assuntos
Adipogenia/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450 , Eicosanoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose/tratamento farmacológico , Obesidade/tratamento farmacológico , Células 3T3-L1 , Adipogenia/genética , Animais , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Intolerância à Glucose/induzido quimicamente , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Camundongos , Camundongos Knockout , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologiaRESUMO
BACKGROUND: The role of oral antibiotic therapy in treating infective endocarditis (IE) is not well established. METHODS: We searched MEDLINE, EMBASE and Scopus for studies in which oral antibiotic therapy was used for the treatment of IE. RESULTS: Seven observational studies evaluating the use oral beta-lactams (five), oral ciprofloxacin in combination with rifampin (one), and linezolid (one) for the treatment of IE caused by susceptible bacteria reported cure rates between 77% and 100%. Two other observational studies using aureomycin or sulfonamide, however, had failure rates >75%. One clinical trial comparing oral amoxicillin versus intravenous ceftriaxone for streptococcal IE reported 100% cure in both arms but its reporting had serious methodological limitations. One small clinical trial (n = 85) comparing oral ciprofloxacin and rifampin versus conventional intravenous antibiotic therapy for uncomplicated right-sided S. aureus IE in intravenous drug users (IVDUs) reported cure rates of 89% and 90% in each arm, respectively (P =0.9); however, drug toxicities were more common in the latter group (62% versus 3%; P <0.01). Major limitations of this trial were lack of allocation concealment and blinding at the delivery of the study drug(s) and assessment of outcomes. CONCLUSION: Reported cure rates for IE treated with oral antibiotic regimens vary widely. The use of oral ciprofloxacin in combination with rifampin for uncomplicated right-sided S. aureus IE in IVDUs is supported by one small clinical trial of relatively good quality and could be considered when conventional IV antibiotic therapy is not possible.
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Antibacterianos/uso terapêutico , Endocardite Bacteriana/tratamento farmacológico , Administração Oral , HumanosRESUMO
The UNC Eshelman School of Pharmacy is transforming its doctor of pharmacy program to emphasize active engagement of students in the classroom, foster scientific inquiry and innovation, and immerse students in patient care early in their education. The admissions process is also being reengineered.
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Educação em Farmácia/tendências , Modelos Educacionais , Currículo , Humanos , North Carolina , Desenvolvimento de Programas , Faculdades de Farmácia , UniversidadesRESUMO
In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals. Blood samples were collected before and 1, 2, 4, 8, and 24 hours after single 1 g oral NAM dose in healthy pregnant (gestational age 24-33 weeks) and nonpregnant female volunteers (n = 6/group). Pooled urine was collected from 0 to 8 hours. NAM, MNA, and M2PY area under the concentration-time curve (AUC) data were analyzed by noncompartmental analysis. No difference in the plasma AUC0â24 of NAM (median (25%-75%): 463 (436-576) vs. 510 (423, 725) µM*hour, P = 0.430) and its intermediate metabolite MNA (89.1 (60.4, 124.4) vs. 83.8 (62.7, 93.7) µM*hour, P = 0.515) was observed in pregnant and nonpregnant volunteers, respectively; however, the terminal metabolite M2PY AUC0 â 24 was significantly lower in pregnant individuals (218 (188, 254) vs. 597 (460, 653) µM*hour, P < 0.001). NAM renal clearance (CLR ; P = 0.184), MNA CLR (P = 0.180), and total metabolite formation clearance (P = 0.405) did not differ across groups; however, M2PY CLR was significantly higher in pregnant individuals (10.5 (9.3-11.3) vs. 7.5 (6.4-8.5) L/h, P = 0.002). These findings demonstrate that the PK of NAM and systemic exposure to its intermediate metabolite MNA are not significantly altered during pregnancy, and systemic exposure to NAM's major metabolite M2PY was reduced during pregnancy due to increased renal elimination.