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- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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- Gong, Y., et al.
(författare)
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Cytochrome P450 oxidase 2J inhibition suppresses choroidal neovascularization in mice
- 2022
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) leads to blindness. It has been widely reported that increased intake of ω−3 long-chain polyunsaturated fatty acids (LCPUFA) diets reduce CNV. Of the three major pathways metabolizing ω−3 (and ω−6 LCPUFA), the cyclooxygenase and lipoxygenase pathways generally produce pro-angiogenic metabolites from ω−6 LCPUFA and anti-angiogenic ones from ω−3 LCPUFA. Howevehr, cytochrome P450 oxidase (CPY) 2C produces pro-angiogenic metabolites from both ω−6 and ω−3 LCPUFA. The effects of CYP2J2 products on ocular neovascularization are still unknown. Understanding how each metabolic pathway affects the protective effect of ω−3 LCPUFA on retinal neovascularization may lead to therapeutic interventions. Objectives: To investigate the effects of LCPUFA metabolites through CYP2J2 pathway and CYP2J2 regulation on CNV both in vivo and ex vivo. Methods: The impact of CYP2J2 overexpression and inhibition on neovascularization in the laser-induced CNV mouse model was assessed. The plasma levels of CYP2J2 metabolites were measured by liquid chromatography and tandem mass spectroscopy. The choroidal explant sprouting assay was used to investigate the effects of CYP2J2 inhibition and specific LCPUFA CYP2J2 metabolites on angiogenesis ex vivo. Results: CNV was exacerbated in Tie2-Cre CYP2J2-overexpressing mice and was associated with increased levels of plasma docosahexaenoic acids. Inhibiting CYP2J2 activity with flunarizine decreased CNV in both ω−6 and ω−3 LCPUFA-fed wild-type mice. In Tie2-Cre CYP2J2-overexpressing mice, flunarizine suppressed CNV by 33 % and 36 % in ω−6, ω−3 LCPUFA diets, respectively, and reduced plasma levels of CYP2J2 metabolites. The pro-angiogenic role of CYP2J2 was corroborated in the choroidal explant sprouting assay. Flunarizine attenuated ex vivo choroidal sprouting, and 19,20-EDP, a ω−3 LCPUFA CYP2J2 metabolite, increased sprouting. The combined inhibition of CYP2J2 with flunarizine and CYP2C8 with montelukast further enhanced CNV suppression via tumor necrosis factor-α suppression. Conclusions: CYP2J2 inhibition augmented the inhibitory effect of ω−3 LCPUFA on CNV. Flunarizine suppressed pathological choroidal angiogenesis, and co-treatment with montelukast inhibiting CYP2C8 further enhanced the effect. CYP2 inhibition might be a viable approach to suppress CNV in AMD. © 2022 Elsevier Inc.
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- Shao, Z., et al.
(författare)
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Cytochrome P450 2C8 omega 3-Long-Chain Polyunsaturated Fatty Acid Metabolites Increase Mouse Retinal Pathologic Neovascularization-Brief Report
- 2014
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 34:3, s. 581-586
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Tidskriftsartikel (refereegranskat)abstract
- Objective Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary 3-long-chain polyunsaturated fatty acids (3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown. Approach and Results The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a 3LCPUFA-enriched diet, retinal neovascularization increases in Tie2-driven human-CYP2C8-overexpressing mice (Tie2-CYP2C8-Tg), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH (Tie2-sEH-Tg). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both 3LCPUFA and 6LCPUFA and antiangiogenic role of sEH in 3LCPUFA metabolism were corroborated in aortic ring assays. Conclusions Our results suggest that CYP2C 3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.
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- Edin, Benoni, et al.
(författare)
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A Bio-inspired approach for the design and characterization of a tactile sensory system for a cybernetic prosthetic hand
- 2006
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Ingår i: Robotics and Automation: Proceedings of the 2006 IEEE International Conference on Robotics and Automation. - 1050-4729. ; , s. 1354-1358
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Tidskriftsartikel (refereegranskat)abstract
- REcent research in prosthetic hands aims at developing innovative cybernetic systems able to allow users to feel an artificial hand as part of their bodies by providing the tactile sensation of a natural hand. Such prostheses must be endowed with artificial proprioceptive and exteroceptive sensory systems as well as appropriate neural interfaces able to exchange sensorymotor signals between the body and the nervous system of an amputee. Based on consideration of available neurophysiological and behavioral data in humans and on the specific sensory needs to control a prototypical grasp-and-lift task, two kinds of sensors were developed: on-off contact sensor arrays and triaxial force sensors. Both sensor types were characterized and compared with their biological counterparts. Their ability to convey critical information durin a lift task was evaluated with the sensors integrated in a biomechatronic cybernetic hand.
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| 8. |
- Edin, Benoni B, et al.
(författare)
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Bio-inspired sensorization of a biomechatronic robot hand for the grasp-and-lift task.
- 2008
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Ingår i: Brain Research Bulletin. - : Elsevier BV. - 0361-9230 .- 1873-2747. ; 75:6, s. 785-95
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Tidskriftsartikel (refereegranskat)abstract
- It has been concluded from numerous neurophysiological studies that humans rely on detecting discrete mechanical events that occur when grasping, lifting and replacing an object, i.e., during a prototypical manipulation task. Such events represent transitions between phases of the evolving manipulation task such as object contact, lift-off, etc., and appear to provide critical information required for the sequential control of the task as well as for corrections and parameterization of the task. We have sensorized a biomechatronic anthropomorphic hand with the goal to detect such mechanical transients. The developed sensors were designed to specifically provide the information about task-relevant discrete events rather than to mimic their biological counterparts. To accomplish this we have developed (1) a contact sensor that can be applied to the surface of the robotic fingers and that show a sensitivity to indentation and a spatial resolution comparable to that of the human glabrous skin, and (2) a sensitive low-noise three-axial force sensor that was embedded in the robotic fingertips and showed a frequency response covering the range observed in biological tactile sensors. We describe the design and fabrication of these sensors, their sensory properties and show representative recordings from the sensors during grasp-and-lift tasks. We show how the combined use of the two sensors is able to provide information about crucial mechanical events during such tasks. We discuss the importance of the sensorized hand as a test bed for low-level grasp controllers and for the development of functional sensory feedback from prosthetic devices.
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