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GS-E3D is an enzymatically modified ginseng extract by pectin lyase. In this study, we evaluated the preventive effects of GS-E3D on blood-retinal barrier (BRB) leakage in a rat model of diabetes. To produce diabetes, rats were injected with streptozotocin. GS-E3D was orally gavaged at 25, 50, and 100 mg/kg body weight for 6 weeks. We then compared the effect of GS-E3D with that of an unmodified ginseng extract (UGE) on retinal vascular leakage. The administration of GS-E3D significantly blocked diabetes-induced BRB breakdown. Immunofluorescence staining showed that GS-E3D reduced the loss of occludin in diabetic rats. In TUNEL staining, the number of apoptotic retinal microvascular cells was dose dependently decreased by GS-E3D treatment. GS-E3D decreased the accumulations of advanced glycation end products in the retinal vessels. In addition, the inhibition potential of GS-E3D on BRB breakage was stronger compared with UGE. These results indicate that GS-E3D could be a beneficial treatment option for preventing diabetes-induced retinal vascular injury.

Retinal apoptosis plays a critical role in the progression of diabetic retinopathy (DR), a common diabetic complication. Currently, the tight control of blood glucose levels is the standard approach to prevent or delay the progression of DR. However, prevalence of DR among diabetic patients remains high. Focusing on natural nutrients or herbal medicines that can prevent or delay the onset of diabetic complications, we administered an ethanol extract of the aerial portion of Osteomeles schwerinae (OSSCE), a Chinese herbal medicine, over a period of 17 weeks to spontaneously diabetic Torii (SDT) rats. OSSCE was found to ameliorate retinal apoptosis through the regulation of advanced glycation end product (AGE) accumulation, oxidative stress, and mitochondrial function via the inhibition of NF-κB activity, in turn, through the downregulation of PKCδ, P47phox, and ERK1/2. We further demonstrated in 25 mM glucose-treated human retinal microvascular endothelial cells (HRMECs) that hyperoside (3-O-galactoside-quercetin), quercitrin (3-O-rhamnoside-quercetin), and 2″-O-acetylvitexin (8-C-(2″-O-acetyl-glucoside)-apigenin) were the active components of OSSCE that mediated its pharmacological action. Our results provide evidence that OSSCE is a powerful agent that may directly mediate a delay in the development or disease improvement in patients of DR.

Background: Aster koraiensis extract (AKE) is a standard dietary herbal supplement. The aim of this study is to investigate the inhibitory effects of AKE on diabetes-induced retinal vascular dysfunction in Spontaneously Diabetic Torii (SDT) rats., Methods: AKE (50 and 100 mg/kg body weight/day) was administered for 16 weeks. The effects of orally administered AKE on blood glucose levels, retinal vascular leakage, apoptosis, and accumulation of advanced glycation end products (AGEs) in the retina were evaluated., Results: SDT rats exhibited hyperglycemia and retinal vascular leakage, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was clearly detected apoptosis in the retinal microvasculature. Immunofluorescence staining revealed the accumulation of AGEs in the retinal vasculature of the SDT rats. However, oral administration of AKE for 16 weeks blocked diabetes-induced blood-retinal barrier (BRB) breakdown and the loss of occludin, which is an important tight junction protein. Apoptosis of retinal vascular cells and AGE accumulation were significantly inhibited after AKE treatment., Conclusion: These results indicate that, as a dietary herbal supplement, AKE may have beneficial effects on patients with diabetic retinopathy.

The aim of the present study was to assess the involvement of the high-mobility group box-1 (HMGB1) protein, receptor for advanced glycation end products (RAGE) and nuclear factor (NF)-κB signaling pathway in the development of diabetic retinopathy. Rat primary retinal pericytes were exposed to 25 mmol/l D‑glucose for 48 h. Diabetic retinal vessels were prepared from streptozotocin-induced diabetic rats 12 weeks following the induction of diabetes. The expression of HMGB1 was detected using immunofluorescence staining. The expression of RAGE and the activity of NF‑κB were analyzed using western blot and electrophoretic mobility shift assays, respectively. The results showed that HMGB1 was translocated to the cytoplasm of the high glucose‑treated pericytes and diabetic retinal pericytes, whereas, in the control cells and the normal retinas, HMGB1 was expressed in the cell nuclei only. The expression of RAGE, a potential receptor for HMGB1, and the activity of NF‑κB were also increased in the high glucose‑treated pericytes, compared with the normal control cells. In addition, high glucose increased the binding of NF‑κB to the RAGE promoter. These findings suggested that the cytoplasmic translocation of HMGB1 may be caused by diabetes and high glucose in retinal pericytes, and that the pathogenic role of HMGB1 may be dependent on the expression of RAGE and activation of NF‑κB.

High-mobility group box-1 (HMGB1) is a well-known pro-inflammatory cytokine. We aimed to investigate the effect of the ethanol extract of the root of P. cuspidatum (PCE) on retinal inflammation in diabetic retinopathy. PCE (100 or 350 mg/kg/day) was administered to diabetic rats for 16 weeks, and hyperglycemia and body weight loss developed in the diabetic rats. The retinal expression levels of HMGB1 and receptor for advanced glycation end products (RAGE) and the activity of nuclear factor-kappa B (NF-κB) in the retina were examined. Additionally, a chromatin immunoprecipitation assay was performed to analyze the binding of NF-κB binding to the RAGE promoter in the diabetic retinas. The levels of HMGB1 and RAGE expression, NF-κB activity, and NF-κB binding to the RAGE promoter were increased in the diabetic retinas. However, treatment with PCE ameliorated the increases in HMGB1 and RAGE expression, and NF-κB activity in the retina. In addition, in diabetic rats, retinal vascular permeability and the loosening of the tight junctions were inhibited by PCE. These findings suggest that PCE has a preventative effect against diabetes-induced vascular permeability by inhibiting HMGB1-RAGE-NF-κB activation in diabetic retinas. The oral administration of PCE may significantly help to suppress the development of diabetic retinopathy in patients with diabetes.

In the pathophysiology of diabetic retinopathy (DR), advanced glycation end products (AGEs) and vascular endothelial growth factor (VEGF) are thought to have important roles. It is known that VEGF causes a breakdown of the blood‑retinal barrier (BRB) and retinal neovascularization; however, how AGEs affect the retina has largely remained elusive. OSSC1E‑K19 is a novel phytochemical component of Osteomeles schwerinae. The objective of the present study was to evaluate the protective effects of OSSC1E‑K19 on retinal vascular injury in AGE‑modified rat serum albumin (AGE-RSA)-induced retinopathy. AGE-RSA-injected rat eyes were used investigate the protective effects of OSSC1E‑K19 on BRB breakdown. Intravitreal injection of OSSC1E-K19 prevented AGE-RSA-induced BRB breakdown and decreased retinal VEGF expression in retinal vessels. In addition, OSSC1E-K19 inhibited the loss of occludin, a significant tight junction protein. These results supported the potential therapeutic utility of OSSC1E-K19 for retinal vascular permeability diseases.

The retinal accumulation of advanced glycation end products (AGEs) is a condition, which is found in diabetic retinopathy. The purpose of the present study was to investigate the protective effect of Litsea japonica extract (LJE) and to elucidate its underlying protective mechanism in model diabetic db/db mice. Male, 7 -week-old db/db mice were treated with LJE (100 or 250 mg/kg body weight) once a day orally for 12 weeks. The expression levels of AGEs and their receptor (RAGE) were subsequently assessed by immunohistochemistry. An electrophoretic mobility shift assay and southwestern histochemistry were used to detect activated nuclear factor κB (NF-κB). The immunohistochemical analysis demonstrated that LJE significantly reduced the expression levels of the AGEs and RAGE in the neural retinas of the db/db mice. LJE markedly inhibited the apoptosis of retinal ganglion cells. In addition, LJE suppressed the activation of NF-κB. These results suggested that LJE may be beneficial for the treatment of diabetes-induced retinal neurodegeneration, and the ability of LJE to attenuate retinal ganglion cell loss may be mediated by inhibition of the accumulation of AGEs.

Many dietary supplements have been sold through advertising their large number of beneficial effects. The aim of this study was to determine whether bilberries (Vaccinium myrtillus) help to prevent diabetes-induced retinal vascular dysfunction in vivo. V. myrtillus extract (VME; 100 mg/kg) was orally administered to streptozotocin-induced diabetic rats for 6 weeks. All diabetic rats exhibited hyperglycemia, and VME did not affect the blood glucose levels and body weight during the experiments. In the fluorescein-dextran angiography, the fluorescein leakage was significantly reduced in diabetic rats treated with VME. VME treatment also decreased markers of diabetic retinopathy, such as retinal vascular endothelial growth factor (VEGF) expression and degradation of zonula occludens-1, occludin and claudin-5 in diabetic rats. In conclusion, VME may prevent or delay the onset of early diabetic retinopathy. These findings have important implications for prevention of diabetic retinopathy using a dietary bilberry supplement.

Loss of blood-retinal barrier (BRB) properties is an important feature in the pathology of diabetic retinopathy. Endothelium integrity is important for the normal vascular function. Litsea japonica (Thunb.) Jussieu is a Korean native plant that is consumed as a vegetable food. In this study, we evaluated the ability of an ethanol extract of L. japonica to prevent retinal vascular leakages in db/db mice, which is an animal model of type II diabetes. L. japonica extracts (LJE, 100 and 250 mg/kg) were administered once a day, orally, for 12 weeks. Vehicle-treated db/db mice exhibited hyperglycemia and retinal vascular leakage. LJE treatment blocked diabetes-induced BRB breakdown and decreased retinal VEGF expression in db/db mice. LJE also inhibited the degradation of occludin, which is an important tight junction protein. These findings support the potential therapeutic usefulness of L. japonica for retinal vascular permeability diseases.

Advanced glycation end products including Nε-(carboxymethyl)lysine (CML) are believed to contribute to retinal pericyte loss in diabetic retinopathy. Nuclear factor-κB (NF-κB) activation has been considered as a potential cytotoxic modulator of retinal pericytes. Herein, we investigated whether CML accumulation can trigger NF-κB activation and apoptosis of retinal pericytes in streptozotocin (STZ)-induced diabetic rats. Seven-week-old Sprague-Dawley rats were made diabetic (STZ, 60 mg/kg). After 5 months, CML level and NF-κB activation were measured in trypsin-digested retinal vessels. In diabetic rats, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive and caspase 3-positive retinal pericytes were significantly increased. CML and NF-κB activation was also markedly increased in diabetic retinal vessels. Moreover, the immunoreactivity of NF-κB was localized within the region where CML were accumulated. Apoptosis occurred in CML-accumulating retinal pericytes. These results suggest that NF-κB could be activated in CML-accumulating pericytes from diabetic retina. CML accumulation is responsible, at least in part, for the apoptosis of retinal pericytes., (Copyright © 2011 S. Karger AG, Basel.)

Aim of the Study: KIOM-79 retards the development of diabetic nephropathy in animal models of type 1 and type 2 diabetes. In this study, we evaluated whether KIOM-79 could prevent apoptotic cell death and advanced glycation end products (AGEs) accumulation in the retinas of diabetic db/db mice., Material and Methods: Mice were treated orally with KIOM-79 (150 mg/kg body weight) once daily for 12 weeks. Levels of retinal ganglion cell death were measured by terminal dUTP nick-end labeling (TUNEL) assay. In the retina, the activity of caspase-3 (a marker of apoptosis) and the formation of AGEs were measured by immunohistochemical staining., Results: KIOM-79 reduced the number of TUNEL-immunoreactive retinal cells. KIOM-79 attenuated caspase-3 expression and AGEs accumulation in the retina., Conclusions: These data show that KIOM-79 can prevent apoptosis in neuronal cells, AGEs accumulation in the retina, and retard the development of diabetic retinopathy.

The accumulation of advanced glycation end products (AGEs) is associated with many of the complications of diabetes mellitus, including diabetic retinopathy. AGE-breakers, such as N-phenacylthiazolium and alagebrium, have been proposed as therapeutic agents for reversing the increase in protein crosslinking in diabetes. (−)-Epicatechin is a major dietary flavonoid with a wide range of health-promoting biological activities. The aim of this study was to determine the potential effect of (−)-epicatechin in reducing the burden of AGEs in vitro and in vivo and to evaluate whether the reduced AGE burden could translate into improvement in retinal vascular function in exogenously AGE-injected rats. Glycated human serum albumin was purified from patients with diabetes. The breakdown of the already formed AGEs was studied by treating glycated human serum albumin with (−)-epicatechin. To study the effect of (−)-epicatechin on retinal vascular function, exogenously AGE-injected rats were treated with (−)-epicatechin (50 and 100 mg/kg i.p.) for two weeks. Apoptosis of retinal vascular cells was quantified using TUNEL staining. The AGE load in the retinas was determined via immunohistochemical staining and western blot analysis. (−)-Epicatechin was able to break preformed glycated human serum albumin in vitro as well as reduce AGE accumulation in retinas in vivo in a dose dependent manner. In exogenously AGE-injected rats, treatment with (−)-epicatechin was evidenced by an improved retinal vascular apoptosis. AGE burden in retinas was also reduced upon treatment. This study suggests that (−)-epicatechin could represent a valuable drug for the treatment of diabetic retinopathy by reducing the AGE burden. [ABSTRACT FROM AUTHOR]

Background: One of the early signs of diabetic retinopathy is the alteration of the blood-retinal barrier (BRB), which may involve the breakdown of endothelial cell tight junctions. Methylglyoxal (MGO) is a cytotoxic metabolite that is produced from glycolysis in vivo. Elevated levels of MGO are observed in a number of pathological conditions, including neurodegenerative disorders and diabetic complications. Herein, we hypothesize that increased levels of MGO disrupt the tight junction protein known as occludin protein by matrix metalloproteinases (MMPs), leading to breakage of the BRB. Methods: MGO was intravitreally injected into eyes of rats. BRB leakage, MMPs activity, and occludin were investigated in intravitreally MGO-injected eyes. Results: When normoglycemic rats were intravitreally injected with 400 μM MGO, there was widespread leakage of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) from the retinal vasculature when compared to control retinas. In addition, MGO-injected retinas demonstrated increases of both activity and expression of MMP-2 and MMP-9, and the degradation of occludin was found in the MGO-injected retinas. Conclusions: The results suggest that the activation of MMPs by elevated levels of MGO in the retina may facilitate an increase in vascular permeability by a mechanism involving proteolytic degradation of occludin. These findings may have implications for the role of MGO in the pathogenesis of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Background: The purpose of the experiment reported here was to assess the involvement of advanced glycation end products (AGEs), oxidative stress, and nuclear factor kappa-B (NF-κB) activation in the development of diabetic keratopathy. Methods: Diabetes was induced by intraperitoneal streptozotocin injection in male Sprague-Dawley rats. The thickness of the cornea was measured. Apoptosis was detected by TUNEL assay and western blot for caspase-3. The expression of AGEs and 8-hydroxydeoxyguanosine (8-OHdG) were studied by immunohistochemistry in corneal tissues of normoglycaemic and diabetic rats. NF-κB activation was evaluated by electrophoretic mobility shift assay and southwestern histochemistry. Results: Corneal edema was observed in diabetic rats. The thickness of cornea was higher in diabetic than in control rats. AGEs were accumulated in corneal tissues. 8-OHdG and NF-κB were identified in corneal epithelium, stroma and endothelium, and its expressions were greater in diabetic than in those of control rats. Diabetes induces significant alterations in rat corneal tissue structure. Conclusions: The higher expression of AGE, 8-OHdG and NF-κB in corneal tissues of diabetic rats suggests that these factors are involved in apoptosis and in subsequent corneal alterations related to diabetic keratopathy. [ABSTRACT FROM AUTHOR]

Increased formation of advanced glycation end products (AGEs) plays an important role in the development of diabetic retinopathy (DR) via blood-retinal barrier (BRB) dysfunction, and reduction of AGEs has been suggested as a therapeutic target for DR. In this study, we examined whether CPA4-1, a herbal combination of Cinnamomi Ramulus and Paeoniae Radix, inhibits AGE formation. CPA4-1 and fenofibrate were tested to ameliorate changes in retinal capillaries and retinal occludin expression in db/db mice, a mouse model of obesity-induced type 2 diabetes. CPA4-1 (100 mg/kg) or fenofibrate (100 mg/kg) were orally administered once a day for 12 weeks. CPA4-1 (the half maximal inhibitory concentration, IC50 = 6.84 ± 0.08 μg/mL) showed approximately 11.44-fold higher inhibitory effect on AGE formation than that of aminoguanidine (AG, the inhibitor of AGEs, IC50 = 78.28 ± 4.24 μg/mL), as well as breaking effect on AGE-bovine serum albumin crosslinking with collagen (IC50 = 1.30 ± 0.37 μg/mL). CPA4-1 treatment ameliorated BRB leakage and tended to increase retinal occludin expression in db/db mice. CPA4-1 or fenofibrate treatment significantly reduced retinal acellular capillary formation in db/db mice. These findings suggested the potential of CPA4-1 as a therapeutic supplement for protection against retinal vascular permeability diseases. [ABSTRACT FROM AUTHOR]

Retinal pericyte loss and neovascularization are characteristic features of diabetic retinopathy. Gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown robust blood-glucose lowering effects in type 2 diabetic patients, but its effects on diabetic retinopathy have not yet been reported. We evaluated the efficacy of gemigliptin on retinal vascular leakage in db/db mice, which is an animal model for type 2 diabetes, and neovascularization in oxygen-induced retinopathy (OIR) mice, which is an animal model for ischemic proliferative retinopathy. Gemigliptin (100 mg/kg/day) was orally administered to the db/db mice for 12 weeks. C57BL/6 mice on postnatal day 7 (P7) were exposed to 75% hyperoxia for 5 days, followed by exposure to room air from P12 to P17 to induce OIR. Gemigliptin (50 mg/kg/day) was intraperitoneally injected daily from P12 to P17. Retinal neovascularization was analyzed in flat-mounted retinas on P17. We determined the efficacy and possible mechanism of gemigliptin on high glucose-induced apoptosis of primary human retinal pericytes. The oral administration of gemigliptin for 4 months significantly ameliorated retinal pericyte apoptosis and vascular leakage in the db/db mice. Gemigliptin also ameliorated retinal neovascularization in the OIR mice. Gemigliptin attenuated the overexpression of plasminogen activator inhibitor-1 (PAI-1) in the retinas of diabetic and OIR mice. Gemigliptin and PAI-1 siRNA significantly inhibited pericyte apoptosis by inhibiting the overexpression of PAI-1, which is induced by high glucose. Our results suggest that gemigliptin has potent anti-angiogenic and anti-apoptotic activities via suppressing DPP-4 and PAI-1, and the results support the direct retinoprotective action of gemigliptin. [ABSTRACT FROM AUTHOR]

Aims of study: The purpose of this study was to investigate the protective effects of KIOM-79, a combination of four plant extracts, on retinal pericytes loss, which is one of the histopathological hallmarks of early diabetic retinopathy. Materials and methods: To investigate the protective effect of KIOM-79 on pericyte apoptosis, we have used methylglyoxal (MGO)-treated primary rat retinal pericytes and retinal vessels from intravitreally MGO-injected eyes. Primary rat retinal pericytes were exposed to 400μM MGO for 6h with or without KIOM-79. 400μM final intravitreal concentration of MGO with or without KIOM-79 (10μg/ml final intravitreal concentration) were intravitreally injected into the right eyes of rats for 2 days. The left eyes were received 3μl of saline only. Retinal vessels were then isolated. We examined apoptosis, ROS productions, 8-OHdG in cultured rat retinal pericytes and retinal vessels. Results: In CCK-8 assay and TUNEL staining, MGO-induced apoptosis of rat retinal pericytes was markedly inhibited by KIOM-79. KIOM-79 significantly reduced intracellular ROS productions and oxidative damage induced by MGO. In addition, the intravitreal injection of KIOM-79 prevented apoptosis of retinal microvascular cells, MGO accumulation and oxidative DNA damage in intravitreally MGO-injected eye. Conclusion: These observations suggest that KIOM-79 acts through an antioxidant mechanism to protect against oxidative stress-induced apoptosis in retinal pericytes. [Copyright &y& Elsevier]