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1.
Int J Mol Sci ; 21(4)2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32054022

RESUMO

The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice were pre-treated with long-acting FGF21 analog or vehicle (Phosphate Buffered Saline; PBS) intraperitoneally (i.p.) before induction of retinal vascular leakage with intravitreal injection of mouse (m) vascular endothelial growth factor 164 (VEGF164) or PBS control. Five hours after mVEGF164 injection, we retro-orbitally injected Fluorescein isothiocyanate (FITC) -dextran and quantified fluorescence intensity as a readout of vascular leakage, using the Image Analysis Module with a machine learning algorithm. In FGF21- or vehicle-treated primary human retinal microvascular endothelial cells (HRMECs), cell permeability was induced with human (h) VEGF165 and evaluated using FITC-dextran and trans-endothelial electrical resistance (TEER). Western blots for tight junction markers were performed. Retinal vascular leakage in vivo was reduced in the FGF21 versus vehicle- treated mice. In HRMECs in vitro, FGF21 versus vehicle prevented hVEGF-induced increase in cell permeability, identified with FITC-dextran. FGF21 significantly preserved TEER compared to hVEGF. Taken together, FGF21 regulates permeability through tight junctions; in particular, FGF21 increases Claudin-1 protein levels in hVEGF-induced HRMECs. Long-acting FGF21 may help reduce retinal vascular leakage in retinal disorders and machine learning assessment can help to standardize vascular leakage quantification.

2.
Int J Mol Sci ; 21(4)2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32098361

RESUMO

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.

3.
Front Neurol ; 10: 1191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798519

RESUMO

Background: Mass effect associated with large or giant aneurysms is an intractable problem for traditional endovascular treatments. Preventing recurrence of aneurysms requires dense coiling, which may aggravate the mass effect. However, the flow diverter (FD) is a new device that avoids the need for dense coiling. This study was performed to investigate whether use of FDs with adjunctive coil embolization can relieve the aneurysmal mass effect and to explore the factors that affect the variation of compressional symptoms. Methods: We retrospectively evaluated patients with compressional symptoms caused by unruptured aneurysms who underwent endovascular treatment with an FD with adjunctive coil embolization at our center from January 2015 to December 2017. Imaging follow-up included digital subtraction angiography (DSA) ranging from 11 to 14 months and magnetic resonance imaging (MRI) ranging from 24 to 30 months; the former was used to evaluate the intracavitary volume, and the latter was used to measure the variation of the mass effect. Follow-up physical examinations were performed to observe variations of symptoms. Results: In total, 22 patients with 22 aneurysms were treated by an FD combined with coil embolization. All 22 patients underwent the last clinical follow-up. Regarding compressional symptoms, 12 (54.54%) patients showed improvement, 6 (27.27%) were fully recovered, and 6 (27.27%) showed improvement but with incomplete cranial palsy. However, five (22.72%) patients showed no change, four (18.18%) showed worsening symptoms compared with their preoperative state, and one (4.55%) died of delayed rupture. Seventeen of the 22 patients underwent MRI. Of these 17 patients, the aneurysm shrank in 13 (76.47%) and no significant change occurred in 4 (23.53%). In the multivariate analysis, a short duration from symptom occurrence to treatment (p = 0.03) and younger patient age (p = 0.038) were statistically significant factors benefiting symptom improvement, and shrinkage of the aneurysm was associated with favorable clinical outcomes (p = 0.006). Conclusions: Use of the FD with adjunctive loose coil embolization might help to alleviate the compressional symptoms caused by intracranial aneurysms. Shrinkage of the aneurysm, a short duration of symptoms, and younger patient age might contribute to favorable outcomes of mass effect-related symptoms.

4.
Bioorg Med Chem Lett ; 29(23): 126709, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629632

RESUMO

Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway.

6.
Front Neurol ; 10: 610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263445

RESUMO

Objective: To evaluate whether the presenting symptoms of VBD predict outcomes following endovascular treatment. Methods: We retrospectively reviewed our institutional clinical database and identified 22 patients (all men; mean age: 52.6 years, range: 11-73 years) with a diagnosis of VBD, who underwent endovascular treatment from January 2010 to December 2017. Results: After analyzing the clinical and imaging data, we evaluated data for 22 symptomatic patients with VBD. At the time of VBD diagnosis, 13 patients (59%) had compressive symptoms, four (18%) had hemorrhagic symptoms, and five (23%) had ischemic symptoms. Nine of the 22 patients (41%), who presented with hemorrhagic and ischemic symptoms, achieved a satisfactory clinical and/or digital subtraction angiography imaging outcome after endovascular treatment. However, of the 13 patients who presented with compressive symptoms, seven (54%, 7/13) died from severe brainstem compression during follow-up; furthermore, magnetic resonance imaging showed worsening of the mass effect in eight patients with compressive symptoms (62%, 8/13). Conclusions: VBD is considered a challenging lesion without an ideal treatment modality. Endovascular treatment of VBD in patients presenting with compressive symptoms at diagnosis may not be beneficial. However, long-term outcomes following endovascular treatment may be acceptable in patients with non-compressive symptoms at diagnosis compared with those with compressive symptoms.

7.
J Vis Exp ; (147)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31157789

RESUMO

In the eye, the embryonic hyaloid vessels nourish the developing lens and retina and regress when the retinal vessels develop. Persistent or failed regression of hyaloid vessels can be seen in diseases such as persistent hyperplastic primary vitreous (PHPV), leading to an obstructed light path and impaired visual function. Understanding the mechanisms underlying the hyaloid vessel regression may lead to new molecular insights into the vascular regression process and potential new ways to manage diseases with persistent hyaloid vessels. Here we describe the procedures for imaging hyaloid in live mice with optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) and a detailed technical protocol of isolating and flat-mounting hyaloid ex vivo for quantitative analysis. Low-density lipoprotein receptor-related protein 5 (LRP5) knockout mice were used as an experimental model of persistent hyaloid vessels, to illustrate the techniques. Together, these techniques may facilitate a thorough assessment of hyaloid vessels as an experimental model of vascular regression and studies on the mechanism of persistent hyaloid vessels.

8.
Mol Ther Nucleic Acids ; 16: 335-347, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-30981984

RESUMO

Pathological angiogenesis is a hallmark of various vascular diseases, including vascular eye disorders. Dysregulation of microRNAs (miRNAs), a group of small regulatory RNAs, has been implicated in the regulation of ocular neovascularization. This study investigated the specific role of microRNA-145 (miR-145) in regulating vascular endothelial cell (EC) function and pathological ocular angiogenesis in a mouse model of oxygen-induced retinopathy (OIR). Expression of miR-145 was significantly upregulated in OIR mouse retinas compared with room air controls. Treatment with synthetic miR-145 inhibitors drastically decreased levels of pathological neovascularization in OIR, without substantially affecting normal developmental angiogenesis. In cultured human retinal ECs, treatment with miR-145 mimics significantly increased the EC angiogenic function, including proliferation, migration, and tubular formation, whereas miR-145 inhibitors attenuated in vitro angiogenesis. Tropomodulin3 (TMOD3), an actin-capping protein, is a direct miR-145 target and is downregulated in OIR retinas. Treatment with miR-145 mimic led to TMOD3 inhibition, altered actin cytoskeletal architecture, and elongation of ECs. Moreover, inhibition of TMOD3 promoted EC angiogenic function and pathological neovascularization in OIR and abolished the vascular effects of miR-145 inhibitors in vitro and in vivo. Overall, our findings indicate that miR-145 is a novel regulator of TMOD3-dependent cytoskeletal architecture and pathological angiogenesis and a potential target for development of treatments for neovascular eye disorders.

9.
Front Neurol ; 10: 179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30915016

RESUMO

Objective: To evaluate the feasibility and effectiveness of the pipeline embolization device (PED) for the treatment of pediatric giant vertebrobasilar dissecting aneurysms (VBDAs). Methods: We retrospectively reviewed our institutional clinical database and identified 2,706 patients who presented with a diagnosis of intracranial aneurysms from January 2016 to June 2018. Among this group, 153 patients were diagnosed with VBDAs, and 54 of these patients underwent PED therapy. The PED technique was used in four patients who were 18 years old or younger at the time of presentation (two males, two females; mean age 9.25 years; age range 8-11 years). Results: All four included pediatric patients were managed with the PED. One patient (25%) was treated with the PED alone, while three (75%) were treated with the PED and coils. One patient died from brainstem infarction or compression of the brainstem, while follow-up of the other three patients revealed favorable outcomes. The mass effect was reduced in cases 1, 2, and 3 on follow-up MRI performed 6 months after the PED procedure. Conclusions: PEDs could be feasible in the treatment of pediatric giant VBDAs. However, the safety and efficacy of this method have not been clarified in this special pediatric population, and long-term follow-up is still necessary.

10.
Prog Retin Eye Res ; 70: 110-133, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30513356

RESUMO

The Wnt signaling pathway plays a pivotal role in vascular morphogenesis in various organs including the eye. Wnt ligands and receptors are key regulators of ocular angiogenesis both during the eye development and in vascular eye diseases. Wnt signaling participates in regulating multiple vascular beds in the eye including regression of the hyaloid vessels, and development of structured layers of vasculature in the retina. Loss-of-function mutations in Wnt signaling components cause rare genetic eye diseases in humans such as Norrie disease, and familial exudative vitreoretinopathy (FEVR) with defective ocular vasculature. On the other hand, experimental studies in more prevalent vascular eye diseases, such as wet age-related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), and corneal neovascularization, suggest that aberrantly increased Wnt signaling is one of the causations for pathological ocular neovascularization, indicating the potential of modulating Wnt signaling to ameliorate pathological angiogenesis in eye diseases. This review recapitulates the key roles of the Wnt signaling pathway during ocular vascular development and in vascular eye diseases, and pharmaceutical approaches targeting the Wnt signaling as potential treatment options.


Assuntos
Doenças Retinianas/fisiopatologia , Vasos Retinianos/fisiopatologia , Via de Sinalização Wnt/fisiologia , Animais , Humanos
11.
Diabetes ; 67(5): 974-985, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29487115

RESUMO

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 insulin-deficient 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-1ß (IL-1ß) mRNA levels. PF-05231023 activated the AKT-nuclear factor erythroid 2-related factor 2 pathway and reduced IL-1ß 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.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Retinopatia Diabética/metabolismo , Fatores de Crescimento de Fibroblastos/farmacologia , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Retinopatia Diabética/etiologia , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Eletrorretinografia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patologia , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neurônios Retinianos/efeitos dos fármacos , Neurônios Retinianos/metabolismo , Neurônios Retinianos/patologia , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
EMBO Mol Med ; 10(1): 76-90, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29180355

RESUMO

The neural cells and factors determining normal vascular growth are not well defined even though vision-threatening neovessel growth, a major cause of blindness in retinopathy of prematurity (ROP) (and diabetic retinopathy), is driven by delayed normal vascular growth. We here examined whether hyperglycemia and low adiponectin (APN) levels delayed normal retinal vascularization, driven primarily by dysregulated photoreceptor metabolism. In premature infants, low APN levels correlated with hyperglycemia and delayed retinal vascular formation. Experimentally in a neonatal mouse model of postnatal hyperglycemia modeling early ROP, hyperglycemia caused photoreceptor dysfunction and delayed neurovascular maturation associated with changes in the APN pathway; recombinant mouse APN or APN receptor agonist AdipoRon treatment normalized vascular growth. APN deficiency decreased retinal mitochondrial metabolic enzyme levels particularly in photoreceptors, suppressed retinal vascular development, and decreased photoreceptor platelet-derived growth factor (Pdgfb). APN pathway activation reversed these effects. Blockade of mitochondrial respiration abolished AdipoRon-induced Pdgfb increase in photoreceptors. Photoreceptor knockdown of Pdgfb delayed retinal vascular formation. Stimulation of the APN pathway might prevent hyperglycemia-associated retinal abnormalities and suppress phase I ROP in premature infants.


Assuntos
Adiponectina/deficiência , Glucose/metabolismo , Hiperglicemia/complicações , Erros Inatos do Metabolismo/complicações , Células Fotorreceptoras de Vertebrados/metabolismo , Vasos Retinianos/crescimento & desenvolvimento , Retinopatia da Prematuridade/etiologia , Adiponectina/metabolismo , Animais , Linhagem Celular , Feminino , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Camundongos Endogâmicos C57BL , Células Fotorreceptoras de Vertebrados/patologia , Neovascularização Retiniana , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia
13.
Opt Express ; 25(22): 26638-26650, 2017 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-29092152

RESUMO

Optomechanics describes the interaction between the optical field and mechanics, and the optomechanical system provides an ideal interface between photons and phonons. The role of the electromagnetic field during optomechanical interaction is studied in this paper as it is regarded as a phonon transmission medium. An analytical model is built to study the phononic mode resonance and reveals the transmission properties of the phonons, which are related to the variance of the frequency of the electromagnetic field. Moreover, when one mechanical mode is driven, different mode resonant properties could be achieved on the transmission spectrum of phonons between the two mechanical modes. We believe that the current work provides significant results for the research of phononic devices.

14.
Invest Ophthalmol Vis Sci ; 58(10): 3862-3870, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28763559

RESUMO

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 (ω3-LCPUFA) correlate with a decreased risk of AMD. Dietary ω3-LCPUFA versus ω6-LCPUFA inhibits mouse ocular neovascularization, but the underlying mechanism needs further exploration. The aim of this study was to investigate if adiponectin (APN) mediated ω3-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% ω3 or 2% ω6-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-AMPKα/AMPKα and qPCR for Apn, Mmps, and IL-10 were used to define mechanism. Results: ω3-LCPUFA intake suppressed laser-induced CNV in WT mice; suppression was abolished with APN deficiency. ω3-LCPUFA, mediated by APN, decreased mouse Mmps expression. APN deficiency decreased AMPKα phosphorylation in vivo and exacerbated choroid-sprouting ex vivo. APN pathway activation inhibited HRMEC proliferation and decreased Mmps. In Vldlr-/- mice, ω3-LCPUFA increased retinal AdipoR1 and inhibited NV. ω3-LCPUFA decreased IL-10 but did not affect Mmps in Vldlr-/- retinas. Conclusions: APN in part mediated ω3-LCPUFA inhibition of neovascularization in two mouse models of AMD. Modulating the APN pathway in conjunction with a ω3-LCPUFA-enriched-diet may augment the beneficial effects of ω3-LCPUFA in AMD patients.


Assuntos
Adiponectina/fisiologia , Neovascularização de Coroide/prevenção & controle , Ácidos Graxos Ômega-3/farmacologia , Degeneração Macular/complicações , Animais , Biomarcadores/metabolismo , Western Blotting , Proliferação de Células/efeitos dos fármacos , Neovascularização de Coroide/metabolismo , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Camundongos , Receptores de Adiponectina/metabolismo
15.
FASEB J ; 31(11): 4665-4681, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28739642

RESUMO

Pathological angiogenesis in the eye is an important feature in the pathophysiology of many vision-threatening diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration, as well as corneal diseases with abnormal angiogenesis. Development of reproducible and reliable animal models of ocular angiogenesis has advanced our understanding of both the normal development and the pathobiology of ocular neovascularization. These models have also proven to be valuable experimental tools with which to easily evaluate potential antiangiogenic therapies beyond eye research. This review summarizes the current available animal models of ocular angiogenesis. Models of retinal and choroidal angiogenesis, including oxygen-induced retinopathy, laser-induced choroidal neovascularization, and transgenic mouse models with deficient or spontaneous retinal/choroidal neovascularization, as well as models with induced corneal angiogenesis, are widely used to investigate the molecular and cellular basis of angiogenic mechanisms. Theoretical concepts and experimental protocols of these models are outlined, as well as their advantages and potential limitations, which may help researchers choose the most suitable models for their investigative work.-Liu, C.-H., Wang, Z., Sun, Y., Chen, J. Animal models of ocular angiogenesis: from development to pathologies.


Assuntos
Neovascularização de Coroide , Retinopatia Diabética , Modelos Animais de Doenças , Neovascularização Retiniana , Animais , Neovascularização de Coroide/genética , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Neovascularização de Coroide/fisiopatologia , Retinopatia Diabética/genética , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Retinopatia Diabética/fisiopatologia , Humanos , Camundongos , Camundongos Transgênicos , Neovascularização Retiniana/genética , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Neovascularização Retiniana/fisiopatologia
16.
FASEB J ; 31(10): 4492-4502, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28646017

RESUMO

Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood. Here we showed that retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor and transcription factor, is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in a mouse model of oxygen-induced proliferative retinopathy. We found that genetic deficiency of RORα substantially induced Sema3e expression in retinopathy. Both RORα and SEMA3E were expressed in retinal ganglion cells. RORα directly bound to a specific ROR response element on the promoter of Sema3e and negatively regulated Sema3e promoter-driven luciferase expression. Suppression of Sema3e using adeno-associated virus 2 carrying short hairpin RNA targeting Sema3e promoted disoriented pathological neovascularization and partially abolished the inhibitory vascular effects of RORα deficiency in retinopathy. Our findings suggest that RORα is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in pathological retinal angiogenesis.-Sun, Y., Liu, C.-H., Wang, Z., Meng, S. S., Burnim, S. B., SanGiovanni, J. P., Kamenecka, T. M., Solt, L. A., Chen, J. RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis.


Assuntos
Glicoproteínas/genética , Proteínas de Membrana/genética , Neovascularização Patológica/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Neovascularização Retiniana/metabolismo , Vasos Retinianos/metabolismo , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas do Citoesqueleto , Células Endoteliais/metabolismo , Glicoproteínas/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Neovascularização Patológica/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Células Ganglionares da Retina , Neovascularização Retiniana/genética
17.
J Exp Med ; 214(6): 1753-1767, 2017 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-28465464

RESUMO

Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases, such as age-related macular degeneration and macular telangiectasia. Ocular neovascularization is strongly associated with inflammation, but the source of inflammatory signals and the mechanisms by which these signals regulate the disruption of avascular privilege in photoreceptors are unknown. In this study, we found that c-Fos, a master inflammatory regulator, was increased in photoreceptors in a model of pathological blood vessels invading photoreceptors: the very low-density lipoprotein receptor-deficient (Vldlr-/- ) mouse. Increased c-Fos induced inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor (TNF), leading to activation of signal transducer and activator of transcription 3 (STAT3) and increased TNFα-induced protein 3 (TNFAIP3) in Vldlr-/- photoreceptors. IL-6 activated the STAT3/vascular endothelial growth factor A (VEGFA) pathway directly, and elevated TNFAIP3 suppressed SOCS3 (suppressor of cytokine signaling 3)-activated STAT3/VEGFA indirectly. Inhibition of c-Fos using photoreceptor-specific AAV (adeno-associated virus)-hRK (human rhodopsin kinase)-sh_c-fos or a chemical inhibitor substantially reduced the pathological neovascularization and rescued visual function in Vldlr-/- mice. These findings suggested that the photoreceptor c-Fos controls blood vessel growth into the normally avascular photoreceptor layer through the inflammatory signal-induced STAT3/VEGFA pathway.


Assuntos
Inflamação/metabolismo , Inflamação/patologia , Células Fotorreceptoras de Vertebrados/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Transdução de Sinais , Animais , Dependovirus/metabolismo , Interleucina-6/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/patologia , RNA Interferente Pequeno/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Retina/fisiopatologia , Retinoides/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Cell Rep ; 18(7): 1606-1613, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28199833

RESUMO

Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis α (TNF-α) expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.


Assuntos
Neovascularização de Coroide/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Retina/efeitos dos fármacos , Neovascularização Retiniana/tratamento farmacológico , Animais , Neovascularização de Coroide/metabolismo , Modelos Animais de Doenças , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/metabolismo , Retina/metabolismo , Neovascularização Retiniana/metabolismo , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Sci Rep ; 6: 38002, 2016 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-27892537

RESUMO

The generation and quantification of quantum entanglement is crucial for quantum information processing. Here we study the transition of Gaussian correlation under the effect of linear optical beam-splitters. We find the single-mode Gaussian coherence acts as the resource in generating Gaussian entanglement for two squeezed states as the input states. With the help of consecutive beam-splitters, single-mode coherence and quantum entanglement can be converted to each other. Our results reveal that by using finite number of beam-splitters, it is possible to extract all the entanglement from the single-mode coherence even if the entanglement is wiped out before each beam-splitter.

20.
EBioMedicine ; 13: 201-211, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27720395

RESUMO

Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)α agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP)2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 long-chain polyunsaturated fatty acids (LCPUFAs). While ω-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both ω-3 and ω-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C ω-3 LCPUFA (and ω-6 LCPUFA) pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPARα-/-mice and augmented ω-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic ω-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPARα. Fenofibrate augmented the overall protective effects of ω-3 LCPUFAs on neovascular eye diseases.


Assuntos
Inibidores da Angiogênese/farmacologia , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Fenofibrato/farmacologia , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Animais , Neovascularização de Coroide/tratamento farmacológico , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , PPAR alfa/metabolismo , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Neovascularização Retiniana/tratamento farmacológico , Transdução de Sinais
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