| 1. |
- Tomita, Y., et al.
(författare)
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Vitreous metabolomics profiling of proliferative diabetic retinopathy
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 64, s. 70-82
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Proliferative diabetic retinopathy (PDR) with retinal neovascularisation (NV) is a leading cause of vision loss. This study identified a set of metabolites that were altered in the vitreous humour of PDR patients compared with non-diabetic control participants. We corroborated changes in vitreous metabolites identified in prior studies and identified novel dysregulated metabolites that may lead to treatment strategies for PDR. Methods We analysed metabolites in vitreous samples from 43 PDR patients and 21 non-diabetic epiretinal membrane control patients from Japan (age 27-80 years) via ultra-high-performance liquid chromatography-mass spectrometry. We then investigated the association of a novel metabolite (creatine) with retinal NV in mouse oxygen-induced retinopathy (OIR). Creatine or vehicle was administered from postnatal day (P)12 to P16 (during induced NV) via oral gavage. P17 retinas were quantified for NV and vaso-obliteration. Results We identified 158 metabolites in vitreous samples that were altered in PDR patients vs control participants. We corroborated increases in pyruvate, lactate, proline and allantoin in PDR, which were identified in prior studies. We also found changes in metabolites not previously identified, including creatine. In human vitreous humour, creatine levels were decreased in PDR patients compared with epiretinal membrane control participants (false-discovery rate <0.001). We validated that lower creatine levels were associated with vascular proliferation in mouse retina in the OIR model (p = 0.027) using retinal metabolomics. Oral creatine supplementation reduced NV compared with vehicle (P12 to P16) in OIR (p = 0.0024). Conclusions/interpretation These results suggest that metabolites from vitreous humour may reflect changes in metabolism that can be used to find pathways influencing retinopathy. Creatine supplementation could be useful to suppress NV in PDR.
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| 2. |
- Gomeniuk, Y. Y., et al.
(författare)
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Electrical properties of high-k LaLuO3 gate oxide for SOI MOSFETs
- 2011
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Ingår i: 6th International Workshop on Semiconductor-on-Insulator Materials and Devices. - 9783037851784 ; , s. 87-93
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Konferensbidrag (refereegranskat)abstract
- The paper presents the results of electrical characterization of MOS capacitors and SOI MOSFETs with novel high-? LaLuO3 dielectric as a gate oxide. The energy distribution of interface state density at LaLuO 3/Si interface is presented and typical maxima of 1.2×10 11 eV-1cm-2 was found at about 0.25 eV from the silicon valence band. The output and transfer characteristics of the n- and p-MOSFET (channel length and width were 1 μm and 50 μm, respectively) are presented. The front channel mobility appeared to be 126 cm2V -1s-1 and 70 cm2V-1s-1 for n- and p-MOSFET, respectively. The front channel threshold voltages as well as the density of states at the back interface are presented.
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| 3. |
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| 4. |
- Cakir, B., et al.
(författare)
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IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants
- 2020
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Ingår i: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:19
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Hyperglycemia, insulin insensitivity, and low IGF1 levels in extremely preterm infants are associated with an increased risk of retinopathy of prematurity (ROP), but the interactions are incompletely understood. METHODS. In 117 extremely preterm infants, serum glucose levels and parenteral glucose intake were recoded daily in the first postnatal week. Serum IGF1 levels were measured weekly. Mice with oxygen-induced retinopathy alone versus oxygen-induced retinopathy plus streptozotocin-induced hyperglycemia/hypoinsulinemia were assessed for glucose, insulin, IGF1, IGFBP1, and IGFBP3 in blood and liver. Recombinant human IGF1 was injected to assess the effect on glucose and retinopathy. RESULTS. The highest mean plasma glucose tertile of infants positively correlated with parenteral glucose intake [r (39) = 0.67, P < 0.0001]. IGF1 plasma levels were lower in the high tertile compared with those in low and intermediate tertiles at day 28 (P = 0.038 and P = 0.03). In high versus lower glucose tertiles, ROP was more prevalent (34 of 39 versus 19 of 39) and more severe (ROP stage 3 or higher; 71% versus 32%). In oxygen-induced retinopathy, hyperglycemia/hypoinsulinemia decreased liver IGF1 expression (P < 0.0001); rh-IGF1 treatment improved normal vascular regrowth (P = 0.027) and reduced neovascularization (P < 0.0001). CONCLUSION. In extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased ROP severity. In a hyperglycemia retinopathy mouse model, decreased insulin signaling suppressed liver IGF1 production, lowered serum IGF1 levels, and increased neovascularization. IGF1 supplementation improved retinal revascularization and decreased pathological neovascularization. The data support IGF1 as a potential treatment for prevention of ROP.
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| 5. |
- Fu, Z., et al.
(författare)
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Fibroblast Growth Factor 21 Protects Photoreceptor Function in Type 1 Diabetic Mice
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:5, s. 974-985
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Tidskriftsartikel (refereegranskat)abstract
- Retinal neuronal abnormalities occur before vascular changes in diabetic retinopathy. Accumulating experimental evidence suggests that neurons control vascular pathology in diabetic and other neovascular retinal diseases. Therefore, normalizing neuronal activity in diabetes may prevent vascular pathology. We investigated whether fibroblast growth factor 21 (FGF21) prevented retinal neuronal dysfunction in insulindeficient diabetic mice. We found that in diabetic neural retina, photoreceptor rather than inner retinal function was most affected and administration of the long-acting FGF21 analog PF-05231023 restored the retinal neuronal functional deficits detected by electroretinography. PF-05231023 administration protected against diabetes-induced disorganization of photoreceptor segments seen in retinal cross section with immunohistochemistry and attenuated the reduction in the thickness of photoreceptor segments measured by optical coherence tomography. PF-05231023, independent of its downstream metabolic modulator adiponectin, reduced inflammatory marker interleukin-1β (IL-1β) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1β expression in stressed photoreceptors. PF-05231023 administration did not change retinal expression of vascular endothelial growth factor A, suggesting a novel therapeutic approach for the prevention of early diabetic retinopathy by protecting photoreceptor function in diabetes.
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| 6. |
- Fu, Z. J., et al.
(författare)
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Adiponectin Mediates Dietary Omega-3 Long-Chain Polyunsaturated Fatty Acid Protection Against Choroidal Neovascularization in Mice
- 2017
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404 .- 1552-5783. ; 58:10, s. 3862-3870
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Neovascular age-related macular degeneration (AMD) is a major cause of legal blindness in the elderly. Diets with omega3-long-chain-polyunsaturated-fatty-acid (omega 3-LCPUFA) correlate with a decreased risk of AMD. Dietary omega 3-LCPUFA versus omega 6-LCPUFA inhibits mouse ocular neovascularization, but the underlying mechanism needs further exploration. The aim of this study was to investigate if adiponectin (APN) mediated x omega 3-LCPUFA suppression of neovessels in AMD. METHODS. The mouse laser-induced choroidal neovascularization (CNV) model was used to mimic some of the inflammatory aspect of AMD. CNV was compared between wild-type (WT) and Apn(-/-) mice fed either otherwise matched diets with 2% x3 or 2% omega 6-LCPUFAs. Vldlr(-/-) mice were used to mimic some of the metabolic aspects of AMD. Choroid assay ex vivo and human retinal microvascular endothelial cell (HRMEC) proliferation assay in vitro was used to investigate the APN pathway in angiogenesis. Western blot for p-AMPK alpha/AMPK alpha and qPCR for Apn, Mmps, and IL-10 were used to define mechanism. RESULTS. omega 3-LCPUFA intake suppressed laser-induced CNV in WT mice; suppression was abolished with APN deficiency. omega 3-LCPUFA, mediated by APN, decreased mouse Mmps expression. APN deficiency decreased AMPK alpha phosphorylation in vivo and exacerbated choroid-sprouting ex vivo. APN pathway activation inhibited HRMEC proliferation and decreased Mmps. In Vldlr(-/-) mice, omega 3-LCPUFA increased retinal AdipoR1 and inhibited NV. omega 3-LCPUFA decreased IL-10 but did not affect Mmps in Vldlr(-/-) retinas. CONCLUSIONS. APN in part mediated omega 3-LCPUFA inhibition of neovascularization in two mouse models of AMD. Modulating the APN pathway in conjunction with a omega 3-LCPUFA-enriched-diet may augment the beneficial effects of omega 3-LCPUFA in AMD patients.
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| 7. |
- Fu, Z. J., et al.
(författare)
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Dyslipidemia in retinal metabolic disorders
- 2019
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Ingår i: Embo Molecular Medicine. - : EMBO. - 1757-4676 .- 1757-4684. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- The light-sensitive photoreceptors in the retina are extremely metabolically demanding and have the highest density of mitochondria of any cell in the body. Both physiological and pathological retinal vascular growth and regression are controlled by photoreceptor energy demands. It is critical to understand the energy demands of photoreceptors and fuel sources supplying them to understand neurovascular diseases. Retinas are very rich in lipids, which are continuously recycled as lipid-rich photoreceptor outer segments are shed and reformed and dietary intake of lipids modulates retinal lipid composition. Lipids (as well as glucose) are fuel substrates for photoreceptor mitochondria. Dyslipidemia contributes to the development and progression of retinal dysfunction in many eye diseases. Here, we review photoreceptor energy demands with a focus on lipid metabolism in retinal neurovascular disorders.
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| 8. |
- Fu, Z. J., et al.
(författare)
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Retinal glial remodeling by FGF21 preserves retinal function during photoreceptor degeneration
- 2021
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Ingår i: Iscience. - : Elsevier BV. - 2589-0042. ; 24:4
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Tidskriftsartikel (refereegranskat)abstract
- The group of retinal degenerations, retinitis pigmentosa (RP), comprises more than 150 genetic abnormalities affecting photoreceptors. Finding degenerative pathways common to all genetic abnormalities may allow general treatment such as neuroprotection. Neuroprotection may include enhancing the function of cells that directly support photoreceptors, retinal pigment epithelial cells, and Muller glia. Treatment with fibroblast growth factor 21 (FGF21), a neuro-protectant, from postnatal week 4-10, during rod and cone loss in P23H mice (an RP model) with retinal degeneration, preserved photoreceptor function and normalized Muller glial cell morphology. Single-cell transcriptomics of retinal cells showed that FGF21 receptor Fgfr1 was specifically expressed in Muller glia/astrocytes. Of all retinal cells, FGF21 predominantly affected genes in Muller glia/astrocytes with increased expression of axon development and synapse formation pathway genes. Therefore, enhancing retinal glial axon and synapse formation with neurons may preserve retinal function in RP and may suggest a general therapeutic approach for retinal degenerative diseases.
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| 9. |
- Fu, Z. J., et al.
(författare)
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Targeting Neurovascular Interaction in Retinal Disorders
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 21:4
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Tidskriftsartikel (refereegranskat)abstract
- The tightly structured neural retina has a unique vascular network comprised of three interconnected plexuses in the inner retina (and choroid for outer retina), which provide oxygen and nutrients to neurons to maintain normal function. Clinical and experimental evidence suggests that neuronal metabolic needs control both normal retinal vascular development and pathological aberrant vascular growth. Particularly, photoreceptors, with the highest density of mitochondria in the body, regulate retinal vascular development by modulating angiogenic and inflammatory factors. Photoreceptor metabolic dysfunction, oxidative stress, and inflammation may cause adaptive but ultimately pathological retinal vascular responses, leading to blindness. Here we focus on the factors involved in neurovascular interactions, which are potential therapeutic targets to decrease energy demand and/or to increase energy production for neovascular retinal disorders.
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| 10. |
- 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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