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Diabetes retinopathy （DR） is an important cause that threatens the visual health of adults. There are some treatment methods of western medicine with definite efficacy， such as anti-vascular endothelial growth factor and laser photocoagulation， but they have many adverse reactions such as intraocular infection and visual field damage. Traditional Chinese medicine （TCM） therapies are safe and effective， which can complement western medicine. Phosphatidylinositol3-kinase （PI3K）/protein kinase B （Akt） signaling pathway regulates a range of processes including glucose metabolism， cell proliferation， and cell transcription and apoptosis， which is closely related to the occurrence and development of DR. Numerous studies have shown that TCM monomers can participate in maintaining the integrity of blood-retinal barrier and inhibiting retinal neovascularization and neurodegeneration in many aspects such as inhibiting oxidative stress and alleviating inflammatory reaction by regulating the PI3K/Akt pathway， so as to delay the progress of DR. Therefore， this study reviewed PI3K/Akt pathway and its relationship with DR， as well as the TCM monomers in interfering with DR based on PI3K/Akt pathway to provide some ideas for the prevention and treatment of DR in integrated TCM and western medicine.
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Age-related macular degeneration(AMD)is a common eye disease causing irreversible visual impairment in the elderly. The tight junction(TJ)between retinal pigment epithelium cells(RPECs)is an important structural unit of the outer blood retinal barrier(oBRB). The TJ is defective in the pathogenesis of AMD, which in turn promotes the destruction of oBRB and accelerates the occurrence and progression of AMD. In this paper, the roles of TJ and TJ protein in maintaining oBRB function, TJ protein abnormality and oBRB destruction in the pathogenesis of AMD were reviewed, aiming to provide new ideas for the treatment of AMD.
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Diabetic retinopathy is the leading cause of blindness in the working-age population, in which diabetic macular edema(DME)is the most common reason resulting in the vision impairment. Studies showed that inflammation factors play an important role in the pathogenesis and development of DME. Chronic hyperglycemia activates several biochemical pathways, leading to retinal hypoxia, oxidative stress and chronic inflammation. Intraretinal inflammation-related cells, such as microglia, monocytes/macrophages, Müller cells and retinal pigment epithelial cells, become activated and release a large number of inflammation-related factors and mediators, including the complement system, vascular endothelial growth factor(VEGF), placental growth factor(PlGF), tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), IL-6 and IL-8, etc., resulting in the breakdown of the blood-retinal barrier and neuronal degeneration. In addition, up-regulatethe expression of intercellular adhesion molecule-1(ICAM-1)and vascular cell adhesion molecule-1(VCAM-1)by retinal vascular endothelial cells increased the adhesion of leukocyte and leukostasis, further aggravating retinal hypoxia and breakdown of the blood-retinal barrier, leading to the increased retinal vascular leakage and macular edema. Therefore, early treatment with anti-VEGF and anti-inflammatory are pivotal for the treatment of DME. In this review, we will discuss the role of inflammation factors in the pathogenesis of DME and the research status of the targeted drugs targeting inflammation, so as to provide reference for the treatment of DME.
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Objective:To investigate the breakdown of blood-retinal outer barrier in the ischemia-reperfusion injury mice following acute intraocular hypertension.Methods:Fifty-seven SPF male C57BL/6J mice were selected and divided into the control group and high-intraocular pressure (IOP) group by using the random number table method.There were 25 mice in the control group and 32 mice in the high-IOP group.After the failure and poor modeling excluded, 20 mice were included in each group, and the left eyes were selected as the experimental eyes.The ischemia-reperfusion injury model of the high-IOP group was established following acute intraocular hypertension by anterior chamber perfusion of 0.9% sodium chloride solution, and the control group only received anterior chamber puncture.Optical coherence tomography was used to detect retinal thickness.Immunofluorescence staining was utilized to identify zonula occludens-1 (ZO-1) protein distribution in retina.Retinal capillary degeneration was identified by trypsin digestion.Inflammatory cell infiltration in retinal sections was observed by hematoxylin and eosin staining.The use and care of the animals complied with the Statement of the Association for Research in Vision and Ophthalmology, and the study protocol was approved by an Ethics Committee of Changsha Aier Eye Hospital (No.2018-KYPJ005).Results:Compared with the control group, the structure of the retinal pigment epithelium (RPE) layer was irregular with obvious exudation and local neuroepithelial detachment and elevation.The thickness of the full retinal layer of mice in the high-IOP group was (235.8±5.3)μm, which was significantly thicker than (213.3±3.9)μm in the control group ( t=3.427, P=0.009). ZO-1 staining results showed that ZO-1 was mainly located in cell membrane and a small part in cytoplasm in the RPE layer of mice.Two days after modeling, ZO-1 in the high-IOP group was significantly internalized with decrease in cell membrane and increase in cytoplasm, and its distribution was irregular.Seven days after modeling, retinal capillary degeneration was observed in the high-IOP group, and the number of degenerated retinal capillaries was 201.0±13.2, which was significantly larger than 11.2±1.7 in the control group ( t=14.280, P<0.01). Hematoxylin-eosin staining results showed that inflammatory cell infiltration, mainly neutrophils, could be observed in the mice retina with high IOP, and the infiltrated inflammatory cells were mainly located under the internal limiting membrane. Conclusions:Acute intraocular hypertension induced retinal ischemia-reperfusion injury in mice destroys the integrity of the outer retinal barriers, and causes granulocyte infiltration in the peripheral circulation, retinal edema as well as retinal capillary degeneration.
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@#The blood-retinal barrier is an important structural basis for maintaining the homeostasis of the retinal environment, but there is still a lack of further research on its complete structure and function. The <i>in vitro</i> blood-retinal barrier model has the characteristics of controllable, efficient, fast and stable, and has become an effective tool to study the specific structure and function of the barrier. This paper mainly reviews the structure, function and <i>in vitro</i> model of blood-retinal barrier, which is helpful to promote the study of physiology, biochemistry, pathopharmacology and clinic of blood-retinal barrier. It also provides a common and key experimental basis for the study of fundus vascular diseases such as diabetic retinopathy.
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@#Cataract is the most common blinding eye disease in our country. Cataract phacoemulsification combined with intraocular lens implantation is the first choice for cataract surgery, with advantages of a small incision, mild anterior chamber reaction, repaid recovery and small astigmatism of corneal. However, there are still some patients failed to achieve ideal visual quality after surgery due to various reasons even if the surgery is successful. Cystoid macular edema(CME)is one of the common complications in pseudophakic eyes affecting postoperative visual quality after cataract surgery. Recent studies on pseudophakic cystoid macular edema(PCME)are reviewed in this paper.
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@#The blood-retinal barrier(BRB)plays an important role in maintaining the homeostasis of the retinal microenvironment. Many diseases can lead to the damage of BRB, such as diabetic retinopathy, acute glaucoma and retinopathy of prematurity. At present, the molecular mechanism of BRB injury has not been fully explained. This paper briefly reviews the structure and function of blood-retina barrier, the damage mechanism of blood-retina barrier caused by various ocular diseases, and the therapeutic countermeasures of drug therapy, laser therapy and surgical treatment.
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ABSTRACT A 26-year-old woman presented at 28 weeks gestation with hypertensive choroidopathy associated with pre-eclampsia. Fundus photography, fundus autofluorescence, spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography, and indocyanine green angiography were performed in both eyes in the immediate postoperative period. SD-OCT images were obtained before delivery and during a 3-month follow-up. Fundus autofluorescence exhibited patchy hyper- and hypoautofluorescent lesions; fluorescein and indocyanine green angiography revealed areas of choroidal ischemia; and SD-OCT showed disorganization of the outer retinal layers and disruption of the ellipsoid zone. After her blood pressure was stabilized, progressive recovery of the outer retinal layer was monitored on SD-OCT.
RESUMO Uma mulher de 26 anos de idade, com 28 semanas de gestação apresentando coroidopatia hipertensiva associada à pré-eclâmpsia. Retinografia, autofluorescência, tomografia de coerência óptica de domínio espectral, angiofluoresceínografia e angiografia com indocianina verde foram realizadas em ambos os olhos no período pós-operatório imediato do parto. Imagens da tomografia de coerência óptica de domínio espectral foram obtidas antes do parto e durante o seguimento de 3 meses. A autofluorescência apresentou lesões heterogêneas hiper e hipoautofluorescentes, a angiofluoresceínografia e angiografia com indocianina verde revelaram áreas de isquemia de coroide, e a tomografia de coerência óptica de domínio espectral apresentou desorganização das camadas externas da retina e interrupção da zona elipsóide. Após a estabilização da pressão sanguínea, a recuperação progressiva da camada externa da retina foi monitorada pela tomografia de coerência óptica de domínio espectral.
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Humans , Female , Pregnancy , Adult , Pre-Eclampsia , Choroid Diseases/etiology , Choroid Diseases/diagnostic imaging , Hypertension/etiology , Hypertension/diagnostic imaging , Remission, Spontaneous , Fluorescein Angiography/methods , Tomography, Optical Coherence/methods , Retinal Pigment Epithelium/pathology , Retinal Pigment Epithelium/diagnostic imagingABSTRACT
@#Diabetic retinopathy(DR), one of the most common complications of diabetes mellitus, is the leading cause of blindness in working-age population. DR, previously regarded as a microvascular disease, is also considered as neuronopathy and low-to-moderate inflammation in retina with research progression. Microglias, the resident macrophage in the inner retina, are responsible for surveillance of the microenvironment in retina. Under abnormal conditions, microglias are activated and interact with different types of cells in retina. In DR, microglias become activated, as evidenced by the activation of the key molecules or signal transduction pathways, such as the nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB)and extracellular signal-regulated kinase(ERK)signaling pathways, which lead to the increased production of pro-inflammatory factors, chemokines,<i> etc.</i> At the same time, the proliferation and migration of activated microglia are enhanced, and microglias migrate to the outer retina. The over-activation of microglias causes neuronal cell apoptosis and blood-retinal barrier breakdown, resulting in vision loss.
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ABSTRACT Purpose: To evaluate the efficacy of prostaglandin antagonists on blood-retinal barrier breakdown induced by anterior segment intraocular simulated surgery. Methods: Rats were randomly assigned to a negative control group, model group, nonsteroidal anti-inflammatory drugs prophylactic treatment group, nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group. Four hours and 48h after modeling, the concentrations of PGE1, PGE2, and PGF2 α in the aqueous humor and vitreous body of the rat model were visualized using ELISA. The integrity of the blood-retinal barrier was quantitatively measured using Evan's blue as a tracer. Results: Four hours after modeling, the concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the negative control group and the nonsteroidal anti-inflammatory drugs prophylactic treatment group were significantly lower than those in the model group. The concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the corticosteroid prophylactic treatment group were higher than those in the negative control group and the nonsteroidal anti-inflammatory drugs prophylactic treatment group. Forty-eight hours after modeling, the concentrations of PGE1, PGE2, and PGF2α in the aqueous humor and vitreous body in the nonsteroidal anti-inflammatory drugs prophylactic treatment group, nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group were lower than those in the model group, but higher than those in the negative group. Retinal Evan's blue leakage in the nonsteroidal anti-inflammatory drugs prophylactic treatment group was higher than that in the negative control group, and lower than those in the nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, corticosteroid treatment group, and model group. Retinal Evan's blue leakage in the nonsteroidal anti-inflammatory drugs treatment group, corticosteroid prophylactic treatment group, and corticosteroid treatment group were lower than those in the model group. Conclusions: This study confirms that prostaglandin antagonists can relieve blood-retinal barrier breakdown in a rat model and that nonsteroidal anti-inflammatory drugs prophylactic treatment can achieve better efficacy.
RESUMO Objetivos: Avaliar a eficácia do antagonista de prostaglandinas no rompimento da barreira hemato-retiniana induzida por cirurgia simulada intraocular do segmento anterior. Métodos: Os ratos foram divididos aleatoriamente em grupo controle negativo, grupo modelo, grupo de tratamento profilático com drogas anti-inflamatórias não esteroides, grupo de tratamento com anti-inflamatórias não esteroides, grupo de tratamento profilático com corticosteroides e grupo de tratamento com corticosteroides. Quatro e 48h após a modelagem, as concentrações de PGE1, PGE2 e PGF2 α no humor aquoso e no corpo vítreo em modelo em ratos foram detectadas através de Elisa. A integridade da barreira hemato-retiniana foi quantitativamente mensurada utilizando o azul de Evans como marcador. Resultados: Quatro horas após a modelagem, as concentrações de PGE1, PGE2 e PGF2α no humor aquoso e no corpo vítreo no grupo controle negativo e no grupo de tratamento profilático com anti-inflamatórias não esteroides foram significativamente menores do que as do grupo modelo. As concentrações de PGE1, PGE2 e PGF2α no humor aquoso e no corpo vítreo no grupo de tratamento profilático com corticosteroides foram maiores do que as observadas no grupo controle negativo e no grupo de tratamento profilático com anti-inflamatórias não esteroides. 48h após a modelagem, as concentrações de PGE1, PGE2 e PGF2α no humor aquoso e no corpo vítreo no grupo de tratamento profilático com anti-inflamatórias não esteroides, no grupo de tratamento com anti-inflamatórias não esteroides, no grupo de tratamento profilático com corticosteroides e no grupo de tratamento com corticosteroides foram menores do que as observadas no grupo modelo e maiores que as observadas no grupo negativo. O extravasamento retinal de azul de Evans no grupo de tratamento profilático com anti-inflamatórias não esteroides foi maior que no grupo controle negativo e menor que nos grupos de tratamento com anti-inflamatórias não esteroides, de tratamento profilático com corticosteroides, de tratamento com corticosteroides e no grupo modelo. O extravasamento retinal de azul de Evans observado nos grupos de tratamento com anti-inflamatórias não esteroides, de tratamento profilático com corticosteroides e de tratamento com corticosteroides foi inferior ao observado no grupo modelo. Conclusões: Este estudo valida que o antagonista das prostaglandinas pode aliviar a ruptura da barreira hemato-retiniana em um modelo em ratos e que o tratamento profilático com anti-inflamatórias não esteroides pode alcançar melhor eficácia.
Subject(s)
Humans , Animals , Male , Rats , Aqueous Humor/drug effects , Prostaglandin Antagonists/administration & dosage , Blood-Retinal Barrier/drug effects , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anterior Eye Segment/surgery , Time Factors , Enzyme-Linked Immunosorbent Assay , Case-Control Studies , Rats, Sprague-Dawley , Models, AnimalABSTRACT
·High altitude retinopathy (HAR) is the pathological changes of retina and optic caused by hypobaric hypoxia when the body is in high altitude environment, and HAR is the major cause of visual loss for the plainsmen who went to high attitude area. With the development of economy and tourism of plateau regions, the prevalence of HAR has recently been increasing for more and more people going to high altitude areas. Currently, it is reported that the pathogenesis of HAR involves a host of mechanisms, including the integrity damage of blood-retinal barrier (BRB),retinal neuron injury,inflammatory mediators and cytokines produced excessively, retinal blood vessels regulate dysfunction, and hemodynamics abnormality,and the synergistic action between them. In this review, we report the findings from current studies on the pathogenesis of HAR, contributing to further studies and diagnosis and treatment.
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Objeetive To evaluate the protective effects of decorin on the inner blood-retinal barrier function under high-glucose plus hypoxia conditions,and explore its potential mechanism.Methods The human umbilical vein endothelial cells (HUVEC) were cultured,and the effect of decorin with different concentrations on HUVEC viability was determined by using the cell counting kit-8 assay (CCK-8).At different hours after incubation under high-glucose plus hypoxia conditions (25 mmol · L-1 D-glucose + 100 μmol · L-1 CoCl2),the suppression effects of various concentrations of decorin on the vascular endothelial growth factor (VEGF) expression of HUVEC was detected by enzyme-linked immunosorbent assay (ELISA).HUVEC were divided into normal control group (5.5 mmol · L-1 D-glucose),high-glucose plus hypoxia group (25 mmol · L-1 D-glucose + 100 μmol · L-1 CoCl2),mannitol control group(5.5 mmol· L-1 D-glucose +19.5 mmol · L-1 mannitol) and decorin treatment group (25 mmol · L-1 D-glucose+ 100 μmol · L-1 CoCl2 + 100 nmol · L-1 decorin).HUVEC barrier function was evaluated by detecting transepithelial electrical resistance (TER) and permeability of fluorescein isothiocyanate-dextran (FITC-dextran).The content of tight junction proteins (claudin-5,occludin,and ZO-1) and p38 mitogen-activated protein kinase (MAPK) phosphorylation were examined by Western blotting.Results According to the results of CCK-8,the survival rates of HUVEC in all groups were more than 90％,different concentrations of decorin showed no significant effect on HUVEC survival (all P ＞ 0.05).According to the results of CCK-8 and ELISA,the stimulation of hypoxia for 48 hours and 100 nmol · L-1 decorin was taken as the condition of further experiment.At 14 days,TER of HUVEC reached its peak of (170.67 ±9.07) Ω.TER of high-glucose plus hypoxia group (97.33 ±6.11)Ω was significantly lower than that of decorin treatment group (157.67 ± 11.72)Ω (P ＜0.05).The FITC-dextran permeability of high-glucose plus hypoxia group increased to (2.12 ±0.07) times of normal control group(P ＜0.05).Decorin reversed this effect to (1.16 ± 0.03) times of normal control group (P ＜ 0.05).The expression of claudin-5,occludin and ZO-1 in high-glucose plns hypoxia group were 0.38 ±0.05,0.43 ±0.02,0.25 ± 0.02,compared to the normal control group (0.72 ±0.05,0.90 ±0.01,0.75 ±0.02),there were statistical differences (all P ＜0.05).The expression of claudin-5,occludin and ZO-1 m decorin treatment group were 0.65 ±0.08,0.87 ±0.03,0.60 ±0.01,there were statistical differences compared with high-glucose plns hypoxia group (all P ＜0.05).The ration of p-p38 MAPK/p38 MAPK in high-glucose plus hypoxia group (0.88 ± 0.02) was increased,while the decorin treatment group (0.58 ± 0.04) reached the level of the normal control group (0.56 ±0.02),there was statistical difference compared with high-glucose plns hypoxia group (P ＜0.05).Conclusion Decorin can protect the HUVEC barrier function under high-glucose plus hypoxia conditions and inhibit the activation of p38 MAPK signaling pathway.So it may be used to treat diabetic retinopathy.
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Background The pathogenesis of diabetic retinopathy (DR) involves a variety of biological pathways.Recently,inflammation factor has been thought to paly an important role in the pathogenesis of DR.Studies show that the concent of tumor necrosis factor-α (TNF-α) is increased in high-glucose environment,which leads to the abnormality of tight junction protein and follows by blood-retinal barrier (BRB) damage.Polysaccharides of dendrobium candidum (PDC) can inhibit the overexpression of TNF-α,but its effect on TNF-α in early DR procedure has been unelucidated.Objective This study was to investigate the effects of PDC on permeability of BRB and its mechanism in daibetic rats.Methods Fifty clear adult SD rats were divided into normal control group,diabetic model group and low-(100 mg/[kg · d]),moderate-(200 mg/[kg · d]) and high-dose (300 mg/[kg · d]) PDC groups,10 rats for each group.Streptozotocin was intraperitoneally injected to establish diabetic model in 40 rats,expect for normal control group.PDC at the concentrations of 100,200 and 300 mg/(kg · d) was intragastrically administered in the low-,moderate-and high-dose groups respectively at 6 weeks after modeling,and normal saline solution was used at the same way in the normal control group and diabetic model group.Evans blue was perfused via cardic chamber and eyes were obtained.Evants blue leakage was measured to evaluate the BRB permeability.The relative expressions of TNF-α,zonula occludens-1 (ZO-1),occludin and claudin-5 proteins were detected by Western blot;TNF-α contents in the retina and serum of the rats were detected by ELISA.Results The leakage concents of Evans blue in the retinas were (12.68±1.30),(30.45±2.60),(22.12±1.15),(17.99±1.00) and (21.49±1.00) in the normal control group,diabetic model goup and low-,moderate-and high-dose PDC groups,respectively,and the retinal leakage concents in the diabetic model group were significantly higher than those in the normal control group,and the retinal leakage contents in the low-,moderate-and high-dose PDC groups were lower than those in the diabetic model group (all at P ＜ 0.01).Western blot showed that the relative expression level of retinal TNF-α was significantly higher in the diabetic model group compared with the normal control group(1.12±0.10 vs.0.27±0.03),and that in the diabetic model group was significantly higher than that in the normal control group;while the relative expression levels of retinal TNF-α in different doses PDC groups were significantly lower,and the relative expression levels of retinal ZO-1,occludin and claudin-5 were significantly higher than those in the diabetic model group (all at P＜0.05).ELISA showed that the concentrations of retinal and serum TNF-α were higher in the diabetic model group compared with the normal control group,and those in the different doses of PDC groups were lower than those in the diabetic model group (all at P＜0.05).No significant differences were found among various doses of PDC groups (all at P＞0.05).Conclusions PDC can improve the permeability of BRB by down-regulating the expression of TNF-α and up-regulating the expressions of tight junction proteins in the retina of diabetic rats,which is probably related to suppressing the development of early DR.
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Objective To observe the effect of different concentration netrin-1 on retinal vascular permeability in diabetes mellitus (DM) rats.Methods Eighty adult Sprague-Dawley rats were randomly divided into 8 groups,10 rats in each group,including normal control group (group A),normal+balanced salt solution (BSS) group (group B),normal+netrin-1 (500 μg/ml) group (group C) and DM group (50 rats in 5 subgroups).DM rats were induced by intraperitoneal injection of streptozocin.Three months after intraperitoneal injection,10 DM rats in the control group were injected with BSS (group D).Forty DM rats were injected with 5 μl of different concentrate netrin-1,and were divided into DM+netrin-1 10 μg/ml group (group E),DM+netrin-1 50 μg/ml group (group F),DM+netrin-1 100 μg/ml group (group G),DM+netrin-1 500 μg/ml group (group H)according to the different concentration.Non-DM rats in group C were injected with netrin-1 500 μg/ml.The expression of occludin was determined by immunohistochemistry for protein,and by real-time fluorescence quantitative reverse transcription polymerase chain reaction for mRNA level.Retinal vascular permeability was measured by Evans blue infusion.Results The expression of occludin protein and mRNA in group D were less than group A (t=27.71,8.59;P=0.00,0.00).However,the retinal vascular permeability increased in group D (t=-42.72,P=0.00).The expression of occluding protein,occludin mRNA and retinal vascular permeability showed significant differences between group D,E,F,G and H (F=146.31,16.54,67.77;P=0.00,0.00,0.00).Compared the group B with group C,there was no significant differences between the expression of occludin protein,occludin mRNA and the retinal vascular permeability (t=-1.13,0.93,1.04;P=0.27,0.36,0.31).The concentrate of netrin-1 showed a significant positive correlation to the expression level of occludin and occludin mRNA (r=0.73,0.81;P=0.00,0.00),but negative correlation to the vascular permeability (r=-0.61,P=0.00).Conclusion Netrin-1 can reduce the DM rats' retinal vascular permeability,which depended on the concentration of netrin-1.
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Aspirin is one of the most important non-steroidal anti-inflammatory drugs,could inhibit cyclooxygenase.It has the antipyretic-analgesic,anti-inflammatory and anti-platelet effects,and has been widely used in preventing heart cerebrovascular disease and rheumatic autoimmune disease.Neovascularization is a self-healing mechanism.However,it also plays the role of the destroyer in cancer and eye diseases at the same time.The pathology of aspirin in the generation of neovascularization,is still in the stage of a fierce debate.On one hand,aspirin has a certain inhibitory effect to the vascular endothelial growth factor (VEGF),which is the strongest factor in neovascularization.On the other hand,aspirin also has the strongest inhibitory effect to endostatin,which is a kind of anti-neovascularization factor.That may lead to the producing of VEGF.Moreover,aspirin may destroy the blood retinal barrier (BRB),which can also cause the formation of retinal neovascularization in a way.Meanwhile,we analyzed the role of aspirin in diseases which can form the neovascular.In the future study,the relationship between aspirin and neovascularization of eye will be further studied.We must measure the pros and cons in the prevention and control of neovascularization when using aspirin.
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The blood–retinal barrier (BRB) alteration is the hallmark feature of diabetic retinopathy. Vascular endothelial growth factor (VEGF) is a potent vasopermeability factor that has been implicated in the pathogenesis of BRB alteration. Inflammation also plays a crucial role in this process with involvement of several chemokines and cytokines. Multiple anti‑VEGF drugs are widely used as in the treatment of diabetic macular edema (DME) as well as proliferative diabetic retinopathy. Several clinical trials have proved the beneficial effects of these drugs in improvement of vision and prevention of vision loss. However, the response to anti‑VEGF drugs in DME is not complete in a significant number of patients. The effect seems transient in this latter group, and many patients do not show complete resolution of fluid. Potential novel therapies targeting molecules beyond VEGF are being developed and examined in clinical trials.
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Objective: To observe the amelioration of ethanol extract from Dendrobium chrysotoxum (EEDC) on non-proliferative diabetic retinopathy (NPDR) induced by streptozotocin (STZ), and further to investigate its engaged mechanism. Methods: NPDR was induced by STZ injection in C57 mice and then the diabetic mice were orally given EEDC. The retinal blood-retinal barrier (BRB) breakdown was evaluated using Evans blue leakage assay. The mRNA expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF) α, early growth response-1 (Egr-1), tissue factor (TF), and Serpine 1 in retinas was detected by real-time PCR. The amount of IL-1β, IL-6, TNF-α, TF, and Serpine 1 in serum was detected by enzyme-linked immunosorbent assay (ELISA). Results: EEDC at both doses reduced the increased Evans blue leakage in STZ-induced NPDR in mice. Results: of Real-Time PCR showed that EEDC reduced the increased retinal mRNA expression of IL-1β, IL-6, TNFα and Egr-1, TF, Serpine 1 in STZ-induced NPDR in mice. ELISA results also confirmed that EEDC reduced the increased serum levels of IL-1β, IL-6, TNF-α, TF, and Serpine 1 in STZ-induced NPDR in mice. Conclusion: EEDC could ameliorate the STZ-induced NPDR in mice via inhibiting retinal BRB breakdown by reducing the expression of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and coagulation-fibrinolysis related signals such as TF and Serpine 1.
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Objective To investigate the protective effect of Niacin on blood-retina barrier (BRB) in diabetic rats and related mechanism.Methods The male Wistar rats (60) were divided into control (CON) group,diabetes (DM) group and Niacin-treated (NA) group,20 rats in each group.Rats diabetes models were induced with streptozotocin injection.Niacin (40 mg/kg · d) was administrated orally everyday in Niacin-treated group until sacrificed after 3 months.Pathological outcomes,total cholesterol (TC) and highdensity lipoprotein (HDL) were evaluated at month 3.Optical microscopy was used to observe the retinal structure.The integrity of BRB and the vascular permeability was quantified by analyzing albumin leakage using Evans blue (EB) method.The relative expressions of Claudin-5,Occludin,zonula occluden (ZO)-1 and GPR109A mRNA in rat retinas were detected by reverse transcription PCR (RT-PCR) and relative expression of GPR109A,tumor necrosis factor (TNF)-α and interleukin (IL)-6 by Western blot.Results Compared to CON group,the TC content was increased and HDL content was decreased in DM group (t=4.034,5.831;P＜0.05).Compared to DM group,the TC content was decreased and HDL content was increased in NA group (t=6.868,3.369;P＜0.05).The retinal structure of CON group was normal.Pathological changes were found in the DM group,such as tumescent nuclei and disorganized structures.The retinal structure of NA group was similar to the control group.Evans blue dye that the microvascular leakage in DM group was increased compared with CON group (t=24.712,P＜0.05),while in NA group was decreased compared with DM group (t =16.414,P＜ 0.05).The mRNA expression of Occludin,Claudin-5,ZO-1 in DM group were decreased compared with CON group (t=11.422,12.638,12.060;P＜ 0.05),while in NA group were increased compared with DM group (t=5.278,3.952,8.030;P＜0.05).The mRNA expression of GPR109A in NA group were increased compared with DM group (t=5.053,P＜ 0.05).The protein expression of GPR109A,IL-6,TNF-αin DM group were increased compared with CON group (t=4.915,11.106,6.582;P＜0.05).Compared to DM group,the protein expression of GPR109A was increased (t=5.806,P＜0.05),while the protein expression of IL-6 and TNF-α were decreased (t=10.131,5.017;P＜0.05).Conclusion Niacin has the protective effect for BRB by up-regulating GPR109A expression which may suppress inflammation.
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The objective of the present study was to elucidate the effect of bisphosphonates, anti-osteoporosis agents, on glucose uptake in retinal capillary endothelial cells under normal and high glucose conditions. The change of glucose uptake by pre-treatment of bisphosphonates at the inner blood-retinal barrier (iBRB) was determined by measuring cellular uptake of [3H]3-O-methyl glucose (3-OMG) using a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB cells) under normal and high glucose conditions. [3H]3-OMG uptake was inhibited by simultaneous treatment of unlabeled D-glucose and 3-OMG as well as glucose transport inhibitor, cytochalasin B. On the other hand, simultaneous treatment of alendronate or pamidronate had no significant inhibitory effect on [3H]3-OMG uptake by TR-iBRB cells. Under high glucose condition of TR-iBRB cells, [3H]3-OMG uptake was increased at 48 h. However, [3H]3-OMG uptake was decreased significantly by pre-treatment of alendronate or pamidronate compared with the values for normal and high glucose conditions. Moreover, geranylgeraniol (GGOH), a mevalonate pathway intermediate, increased the uptake of [3H]3-OMG reduced by bisphosphonates pre-treatment. But, pre-treatment of histamine did not show significant inhibition of [3H]3-OMG uptake. The glucose uptake may be down regulated by inhibiting the mevalonate pathway with pre-treatment of bisphosphonates in TR-iBRB cells at high glucose condition.
Subject(s)
Animals , Rats , Alendronate , Blood-Retinal Barrier , Capillaries , Cytochalasin B , Diphosphonates , Endothelial Cells , Glucose , Hand , Histamine , Mevalonic Acid , RetinaldehydeABSTRACT
Background Retina fixed flat-mount perfused by Evans blue (EB) is a common method for the evaluation of blood-retinal barrier (BRB).However,previous method is inconvenient for some laboratories because the retinal specimen can not be observed by gereral microscope rather than confocal laser scanning microscope after the fixation.Objective This study was to modify the preparing way of flat-mounted retina in order to obtain transparent specimen for the observation of rat retinal vessels and the evaluation of leakage under the ordinary fluorescence microscope.Methods Forty male SD rats were divided into the control group,diabetes mellitus (DM) 1-month group,DM 3-month group and DM 6-month group according to the random number table.Streptozotocinum (STZ) of 2％ dissolved in 0.05 mmol/L sodium citrate-hydrochloric acid buffer was intraperitoneally injected in SD rats to establish DM models,and the equal volume of solvent was injected in the same way in the control rats.One month,three months and six months after injection,EB of 30 g/L was injected via rat femoral vein in the dose of 45 mg/kg.Fifteen minutes after injection of EB,the rats were sacrificed and the retinas were isolated and cut radially to prepare the flat-mounted retinas in PBS immediately and then were dried till the specimens were transparent.The specimens were examined under the fluorescence microscope.The percentage of EB leakage was quantitatively calculated by IPP 6.0 software.All procedures were performed following approval of the institutional animal care and use committee of Tianjin Medical University.Results The retina morphology was normal in the control group,and EB filled the vessels,exhibiting the red fluorescence under the fluorescence microscope.Compared with the control group,retinal background fluorescence was enhanced slightly in the DM 1-month group,and focal leakage of the EB from capillaries and focal dilated vessels were found in the DM 3-month group,further,vascular caliber inequality,retinal hypoperfusion area and a larger number of hyperfluorescence areas were seen in the DM 6-month group.The percentage of leakage area was (0.05 ±0.02) ％,(0.27 ±0.06) ％,(1.17 ±0.18)％ and (4.77 ±0.66)％ in the control group,DM 1-month group,DM 3-month group and DM 6-month group,respectively,showing a significant difference among the four groups (F =795.800,P＜0.001),and the leakage area was obviously larger in the DM 3-month group and DM 6-month group than that in thecontrol group (q'=10.338,q'=43.475,both at P＜0.001).Conclusions Modified EB-perfused retinal wholemount method is easy and helpful for clear visualization of retinal vessel leakage induced by BRB breakdown in the diabetic rats under the common fluorescence microscope.