One-Year Outcomes of a Treat-and-Extend Regimen of Aflibercept for Exudative Age-Related Macular Degeneration.

PURPOSE: The aim of this study was to investigate the 1-year outcomes of treat-and-extend aflibercept for exudative age-related macular degeneration (AMD) in Japan. PROCEDURES: Clinical records of 67 patients (67 eyes) were reviewed. Monthly aflibercept was administered until resolution of exudation and maximal reduction of pigment epithelial detachment. Injection intervals were extended by 2-week units up to 12 weeks if no exudation was observed and shortened for recurrence. RESULTS: Mean best-corrected visual acuity (logarithm of the minimum angle of resolution) improved from 0.29 to 0.14 at 12 months (p < 0.0001). Mean central retinal thickness decreased from 430 µm to 236 µm at 12 months (p < 0.0001). Fifty-nine eyes (88.0%) achieved a dry macula with a mean of 8.3 injections by study end. The injection interval was extended to 10 weeks in 44.8% and to 12 weeks in 17.9% of eyes. CONCLUSIONS: At 1 year, good outcomes were obtained using treat-and-extend aflibercept for exudative AMD in Japan.

Structural and functional associations of the rostral anterior cingulate cortex with subjective happiness.

Happiness is one of the most fundamental human goals, which has led researchers to examine the source of individual happiness. Happiness has usually been discussed regarding two aspects (a temporary positive emotion and a trait-like long-term sense of being happy) that are interrelated; for example, individuals with a high level of trait-like subjective happiness tend to rate events as more pleasant. In this study, we hypothesized that the interaction between the two aspects of happiness could be explained by the interaction between structure and function in certain brain regions. Thus, we first assessed the association between gray matter density (GMD) of healthy participants and trait-like subjective happiness using voxel-based morphometry (VBM). Further, to assess the association between the GMD and brain function, we conducted functional magnetic resonance imaging (MRI) using the task of positive emotion induction (imagination of several emotional life events). VBM indicated that the subjective happiness was positively correlated with the GMD of the rostral anterior cingulate cortex (rACC). Functional MRI demonstrated that experimentally induced temporal happy feelings were positively correlated with subjective happiness level and rACC activity. The rACC response to positive events was also positively correlated with its GMD. These results provide convergent structural and functional evidence that the rACC is related to happiness and suggest that the interaction between structure and function in the rACC may explain the trait-state interaction in happiness.

Interaction of numerosity and time in prefrontal and parietal cortex.

It has been proposed that numerical and temporal information are processed by partially overlapping magnitude systems. Interactions across different magnitude domains could occur both at the level of perception and decision-making. However, their neural correlates have been elusive. Here, using functional magnetic resonance imaging in humans, we show that the right intraparietal cortex (IPC) and inferior frontal gyrus (IFG) are jointly activated by duration and numerosity discrimination tasks, with a congruency effect in the right IFG. To determine whether the IPC and the IFG are involved in response conflict (or facilitation) or modulation of subjective passage of time by numerical information, we examined their functional roles using transcranial magnetic stimulation (TMS) and two different numerosity-time interaction tasks: duration discrimination and time reproduction tasks. Our results show that TMS of the right IFG impairs categorical duration discrimination, whereas that of the right IPC modulates the degree of influence of numerosity on time perception and impairs precise time estimation. These results indicate that the right IFG is specifically involved at the categorical decision stage, whereas bleeding of numerosity information on perception of time occurs within the IPC. Together, our findings suggest a two-stage model of numerosity-time interactions whereby the interaction at the perceptual level occurs within the parietal region and the interaction at categorical decisions takes place in the prefrontal cortex.

Beneficial effects of vildagliptin on retinal injury in obese type 2 diabetic rats.

BACKGROUND/AIMS: Vildagliptin is an oral inhibitor of dipeptidyl peptidase-4, an enzyme mainly responsible for inactivating incretins, and one of the widely used drugs for the treatment of type 2 diabetes. However, effects of vildagliptin on retinal injury in diabetes remain unclear. We examined here whether oral administration of vildagliptin inhibited gene expression of inflammatory and thrombogenic parameters in Otsuka Long-Evans Tokushima Fatty rats (OLETF rats), an animal model of obese type 2 diabetes. METHODS: OLETF rats at 22 weeks of age were given vehicle or 3 mg/kg of vildagliptin for another 10 weeks. Gene expression was analyzed in quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Vildagliptin significantly inhibited the increase in body weight and decreased average fasting blood glucose in the OLETF rats. Compared with 22-week-old OLETF rats, gene expression levels of vascular endothelial growth factor, intercellular adhesion molecule-1, plasminogen activator inhibitor-1 and pigment epithelium-derived factor were significantly increased in the retinas of OLETF rats at 32 weeks of age, all of which were inhibited by treatment with vildagliptin. CONCLUSIONS: The present study demonstrated for the first time that vildagliptin inhibited inflammatory and thrombogenic reactions in the retinas of obese type 2 diabetic rats. Vildagliptin may play a protective role against diabetic retinopathy.

Pigment epithelium-derived factor (PEDF) inhibits proximal tubular cell injury in early diabetic nephropathy by suppressing advanced glycation end products (AGEs)-receptor (RAGE) axis.

Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein with anti-angiogenic and anti-inflammatory properties, and it could block the development and progression of experimental diabetic retinopathy. However, a role for PEDF in early experimental diabetic nephropathy is not fully understood. Advanced glycation end products (AGEs) and their receptor (RAGE) axis stimulates oxidative stress generation and subsequently evokes inflammatory and fibrogenic reactions in renal tubular cells, thereby playing a role in diabetic nephropathy. Therefore, this study investigated whether PEDF could prevent AGE-elicited tubular cell injury in early diabetic nephropathy. Human proximal tubular cells were incubated with or without AGE-bovine serum albumin in the presence or absence of PEDF. Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Gene expression was analyzed by quantitative real-time reverse transcription-polymerase chain reactions. Reactive oxygen species (ROS) was measured with dihydroethidium staining. PEDF or antibodies raised against RAGE inhibited the AGE-induced RAGE gene expression and subsequently reduced ROS generation, monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-ß (TGF-ß), fibronectin and type IV collagen mRNA levels in proximal tubular cells. RAGE gene expression, ROS generation and MCP-1 and TGF-ß mRNA levels were significantly increased in diabetic kidney, which were suppressed by administration of PEDF. Our present data suggest that PEDF could play a protective role against tubular injury in diabetic nephropathy by attenuating the deleterious effects of AGEs via down-regulation of RAGE expression. Administration of PEDF may offer a promising strategy for halting the development of diabetic nephropathy.

Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy.

BACKGROUND: Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, thus suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. We investigated here whether and how PEDF could prevent the development of diabetic retinopathy. METHODS: Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Early neuronal derangements were evaluated by electroretinogram (ERG) and immunofluorescent staining of glial fibrillary acidic protein (GFAP). Expression of PEDF and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress, was localized by immunofluorescence. Vascular endothelial growth factor (VEGF) and p22phox expression were evaluated with western blots. Breakdown of blood retinal barrier (BRB) was quantified with fluorescein isothiocynate (FITC)-conjugated dextran. NADPH oxidase activity was measured with lucigenin luminescence. RESULTS: Retinal PEDF levels were reduced, and amplitudes of a- and b-wave in the ERG were decreased in diabetic rats, which were in parallel with GFAP overexpression in the Müller cells. Further, retinal 8-OHdG, p22phox and VEGF levels and NADPH oxidase activity were increased, and BRB was broken in diabetic rats. Administration of PEDF ameliorated all of the characteristic changes in early diabetic retinopathy. CONCLUSIONS: Results suggest that PEDF could prevent neuronal derangements and vascular hyperpermeability in early diabetic retinopathy via inhibition of NADPH oxidase-driven oxidative stress generation. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.

Administration of pigment epithelium-derived factor (PEDF) inhibits cold injury-induced brain edema in mice.

Brain edema is the most life-threatening complication that occurs as a result of a number of insults to the brain. However, its therapeutic options are insufficiently effective. We have recently found that administration of pigment epithelium-derived factor (PEDF) inhibits retinal hyperpermeability in rats by counteracting biological effects of vascular endothelial growth factor (VEGF). In this study, we investigated whether PEDF could inhibit cold injury-induced brain edema in mice. Cold injury was induced by applying a pre-cooled metal probe on the parietal skull. VEGF and its receptor Flk-1 gene and/or protein expressions were up-regulated in the cold-injured brain. Cold injury induced brain edema, which was reduced by intraperitoneal injection of VEGF antibodies (Abs) or apocynin, an inhibitor of NADPH oxidase. PEDF mRNA and protein levels were up-regulated in response to cold injury. PEDF dose-dependently inhibited the brain edema, whose effect was neutralized by simultaneous treatments with anti-PEDF Abs. Although VEGF and Flk-1 gene and/or protein expressions were not suppressed by PEDF, PEDF or anti-VEGF Abs inhibited the cold injury-induced NADPH oxidase activity in the brain. Further, PEDF treatment inhibited activation of Rac-1, an essential component of NADPH oxidase in the cold-injured brain, while it did not affect mRNA levels of gp91phox, p22phox, or Rac-1. These results demonstrate that PEDF could inhibit the cold injury-induced brain edema by blocking the VEGF signaling to hyperpermeability through the suppression of NADPH oxidase via inhibition of Rac-1 activation. Our present study suggests that PEDF may be a novel therapeutic agent for the treatment of brain edema.

Increased levels of pigment epithelium-derived factor in aqueous humor of patients with uveitis.

AIM: To evaluate whether aqueous humor levels of pigment epithelium-derived factor (PEDF) are increased in patients with uveitis METHODS: Aqueous humor levels of PEDF and tumour necrosis factor alpha (TNFalpha) were determined by ELISA in 34 uveitis samples and 9 cataract control samples. RESULTS: Aqueous humor PEDF and TNFalpha levels were significantly higher in patients with uveitis than in controls (mean (SD) 6.4 (0.8) v 1.3 (0.2) microg/ml and 14.7 (3.8) v 4.2 (0.4) pg/ml, respectively; p<0.01). A positive correlation between PEDF and TNFalpha was found in patients with uveitis (r = 0.40, p<0.01). Furthermore, PEDF levels in aqueous humor were increased in proportion to the disease activity of uveitis. CONCLUSION: The results show that aqueous humor levels of PEDF are increased in patients with uveitis. Our observations suggest that aqueous humor levels of PEDF may be increased as a countersystem against inflammation in uveitis.

Positive correlation between pigment epithelium-derived factor and monocyte chemoattractant protein-1 levels in the aqueous humour of patients with uveitis.

AIM: To evaluate whether aqueous humour levels of pigment epithelium-derived factor (PEDF) are associated with monocyte chemoattractant protein-1 (MCP-1) in patients with uveitis. METHODS: Aqueous humour levels of MCP-1 and PEDF were determined by ELISA in 34 uveitis samples and 9 cataract control samples. RESULTS: Aqueous humour MCP-1 and PEDF levels were significantly higher in patients with infectious or non-infectious uveitis than in controls (mean (SD) 32.3 (10.7) ng/ml vs 4.48 (1.10) ng/ml vs 0.47 (0.10) ng/ml, and 8.40 (1.30) microg/ml vs 5.01 (0.92) microg/ml vs 1.32 (0.22) microg/ml, respectively, p<0.001). A positive correlation between PEDF and MCP-1 was found in patients with uveitis (r = 0.39, p<0.01). CONCLUSION: The results demonstrated that aqueous humour levels of PEDF were positively associated with MCP-1 in patients with uveitis. The present observations suggest that aqueous humour levels of PEDF may be a marker of inflammation in uveitis.

Positive correlation of pigment epithelium-derived factor and total antioxidant capacity in aqueous humour of patients with uveitis and proliferative diabetic retinopathy.

BACKGROUND/AIMS: There are several animal studies to suggest that pigment epithelium-derived factor (PEDF) may exert beneficial effects on diabetic retinopathy and uveitis by acting as an endogenous antioxidant. However, the interrelationship between PEDF and total antioxidant capacity in the human eye remains to be elucidated. In this study, PEDF and total antioxidant levels were determined in the aqueous humour of patients with proliferative diabetic retinopathy (PDR) and uveitis, and the relationship between these two markers was investigated. METHODS: Aqueous humour levels of PEDF and total antioxidant capacity were determined by an ELISA system in 34 uveitis and 9 PDR samples. RESULTS: Aqueous humour levels of PEDF and total antioxidant capacity were significantly lower in patients with PDR than those with uveitis (1.8+/-0.2 microg/ml vs 6.4+/-0.8 microg/ml and 0.17+/-0.03 mmol/l vs 0.85+/-0.05 mmol/l, respectively, p<0.01). A positive correlation between PEDF and total antioxidant capacity was found in patients with PDR and uveitis (r = 0.33, p<0.05). CONCLUSION: This study demonstrated that PEDF levels were associated with total antioxidant capacity in aqueous humour levels in humans. These observations suggest that substitution of PEDF may be a therapeutic target for oxidative stress-involved eye diseases, especially PDR.

Positive association of pigment epithelium-derived factor with total antioxidant capacity in the vitreous fluid of patients with proliferative diabetic retinopathy.

BACKGROUND: Pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, was recently found to inhibit advanced glycation end product (AGE)-induced retinal hyperpermeability and angiogenesis through its antioxidative properties, suggesting that it may exert beneficial effects on diabetic retinopathy by acting as an endogenous antioxidant. However, the inter-relationship between PEDF and total antioxidant capacity in the eye remains to be elucidated. AIMS: To determine vitreous PEDF and total antioxidant levels in patients with proliferative diabetic retinopathy (PDR), and to investigate the relationship between them. METHODS: Vitreous levels of PEDF and total antioxidant capacity were measured by an ELISA in 39 eyes of 36 patients with diabetes and PDR and in 29 eyes of 29 controls without diabetes. RESULTS: Vitreous levels of total antioxidant capacity were significantly lower in patients with diabetes and PDR than in controls (mean (SD) 0.16 (0.05) vs 0.24 (0.09) mmol/l, respectively, p<0.001). PEDF levels correlated positively with total antioxidant status in the vitreous of patients with PDR (r = 0.37, p<0.05) and in controls (r = 0.41, p<0.05). Further, vitreous levels of PEDF in patients with PDR without vitreous haemorrhage (VH(-)) were significantly (p<0.05) decreased, compared with those in the controls or in patients with PDR with vitreous haemorrhage (VH(+); PDR VH(-), 4.5 (1.1) microg/ml; control, 7.4 (4.1) microg/ml; PDR VH(+) 8.5 (3.6) microg/ml). CONCLUSION: This study demonstrates that PEDF levels are associated with total antioxidant capacity of vitreous fluid in humans, and suggests that PEDF may act as an endogenous antioxidant in the eye and could play a protective role against PDR.

Pediatric endogenous Haemophilus influenzae endophthalmitis with presumed hyposplenism.

BACKGROUND: Endogenous bacterial endophthalmitis is a rare but potentially devastating intraocular infection that can have severe sight-threatening complications. Most patients with endogenous bacterial endophthalmitis have underlying infectious conditions, such as diabetes or malignancy, which predispose them to infection. CASE REPORT: A 1-year-old girl presented with cloudiness of the right eye. Ocular examination showed a cloudy cornea in the right eye with conjunctival injection and hypopyon. The intraocular pressure was 43 mmHg, and the fundus could not be visualized. She had an 8-day history of fever, and cerebrospinal fluid analysis showed typical findings of bacterial meningitis. She was clinically diagnosed with bacterial meningitis and endophthalmitis in the right eye and was treated with intravenous, topical, and intravitreal antibiotics and vitrectomy. Haemophilus influenzae was isolated from the blood and cerebrospinal fluid cultures, but not from the aqueous and vitreous cultures. Four months later, her pediatrician diagnosed Streptococcus pneumoniae meningitis, but she had no clinical signs of endophthalmitis. Seven years after the initial presentation, the best-corrected visual acuity was 20/40 in the right eye. DISCUSSION: Endophthalmitis caused by H. influenzae is generally associated with poor visual outcomes; however, the patient in the current case responded well to the treatment. The patient had recurrent bacterial meningitis caused by H. influenzae and S. pneumoniae within a 4-month period. Magnetic resonance imaging was performed to search for underlying infectious causes and revealed that the patient had an extremely small spleen for her age. Because the spleen is critical for clearing encapsulated bacteria such as H. influenzae or S. pneumoniae, we speculated that hyposplenism led to the bloodstream infection of H. influenza and then endogenous endophthalmitis in the right eye.

The role of prosody and context in sarcasm comprehension: Behavioral and fMRI evidence.

A hearer's perception of an utterance as sarcastic depends on integration of the heard statement, the discourse context, and the prosody of the utterance, as well as evaluation of the incongruity among these aspects. The effect of prosody in sarcasm comprehension is evident in everyday conversation, but little is known about its underlying mechanism or neural substrates. To elucidate the neural underpinnings of sarcasm comprehension in the auditory modality, we conducted a functional MRI experiment with 21 adult participants. The participants were provided with a short vignette in which a child had done either a good or bad deed, about which a parent made a positive comment. The participants were required to judge the degree of the sarcasm in the parent's positive comment (praise), which was accompanied by either positive or negative affective prosody. The behavioral data revealed that an incongruent combination of utterance and the context (i.e., the parent's positive comment on a bad deed by the child) induced perception of sarcasm. There was a significant interaction between context and prosody: sarcasm perception was enhanced when positive prosody was used in the context of a bad deed or, vice versa, when negative prosody was used in the context of a good deed. The corresponding interaction effect was observed in the rostro-ventral portion of the left inferior frontal gyrus corresponding to Brodmann's Area (BA) 47. Negative prosody incongruent with a positive utterance (praise) activated the bilateral insula extending to the right inferior frontal gyrus, anterior cingulate cortex, and brainstem. Our findings provide evidence that the left inferior frontal gyrus, particularly BA 47, is involved in integration of discourse context and utterance with affective prosody in the comprehension of sarcasm.

The Brain Mechanisms Underlying the Perception of Pungent Taste of Capsaicin and the Subsequent Autonomic Responses.

In a human fMRI study, it has been demonstrated that tasting and ingesting capsaicin activate the ventral part of the middle and posterior short gyri (M/PSG) of the insula which is known as the primary gustatory area, suggesting that capsaicin is recognized as a taste. Tasting and digesting spicy foods containing capsaicin induce various physiological responses such as perspiration from face, salivation, and facilitation of cardiovascular activity, which are thought to be caused through viscero-visceral autonomic reflexes. However, this does not necessarily exclude the possibility of the involvement of higher-order sensory-motor integration between the M/PSG and anterior short gyrus (ASG) known as the autonomic region of the insula. To reveal a possible functional coordination between the M/PSG and ASG, we here addressed whether capsaicin increases neural activity in the ASG as well as the M/PSG using fMRI and a custom-made taste delivery system. Twenty subjects participated in this study, and three tastant solutions: capsaicin, NaCl, and artificial saliva (AS) were used. Group analyses with the regions activated by capsaicin revealed significant activations in the bilateral ASG and M/PSG. The fMRI blood oxygenation level-dependent (BOLD) signals in response to capsaicin stimulation were significantly higher in ASG than in M/PSG regardless of the side. Concomitantly, capsaicin increased the fingertip temperature significantly. Although there was no significant correlation between the fingertip temperatures and BOLD signals in the ASG or M/PSG when the contrast [Capsaicin-AS] or [Capsaicin-NaCl] was computed, a significant correlation was found in the bilateral ASG when the contrast [2 × Capsaicin-NaCl-AS] was computed. In contrast, there was a significant correlation in the hypothalamus regardless of the contrasts. Furthermore, there was a significant correlation between M/PSG and ASG. These results indicate that capsaicin increases neural activity in the ASG as well as the M/PSG, suggesting that the neural coordination between the two cortical areas may be involved in autonomic responses to tasting spicy foods as reflected in fingertip temperature increases.

Genomics approach to abscisic acid- and gibberellin-responsive genes in rice.

We used an 8987-EST collection to construct a cDNA microarray system with various genomics information (full-length cDNA, expression profile, high accuracy genome sequence, phenotype, genetic map, and physical map) in rice. This array was used as a probe to hybridize target RNAs prepared from normally grown callus of rice and from callus treated for 6 hr or 3 days with the hormones abscisic acid (ABA) or gibberellin (GA). We identified 509 clones, including many clones that had never been annotated as ABA-or GA-responsive. These genes included not only ABA- or GA-responsive genes but also genes responsive to other physiological conditions such as pathogen infection, heat shock, and metal ion stress. Comparison of ABA- and GA-responsive genes revealed antagonistic regulation for these genes by both hormones except for one defense-related gene, thionin. The gene for thionin was up-regulated by both hormone treatments for 3 days. The upstream regions of all the genes that were regulated by both hormones had cis-elements for ABA and GA response. We performed a clustering analysis of genes regulated by both hormones and various expression profiles that showed three notable clusters (seed tissues, low temperature and sugar starvation, and thionin-gene related). A comparison of the cis-elements for hormone response genes between rice and Arabidopsis thaliana, we identified cis-elements for dehydration-stress response or for expression of amylase gene as Arabidopsis gene-specific or rice gene-specific, respectively.

The neural substrates of the warning effect: a functional magnetic resonance imaging study.

To test the hypothesis the warning effect is mediated by the top-down attentional modulation of the motor system, we conducted functional MRI using a Go/No-Go task with visual and auditory warning stimuli. For aurally-warned, visually-prompted trials, the auditory warning stimulus was presented for 1500ms, during which visual cues were presented that prompted either Go or No-Go responses. The same format was used for visually-warned, aurally-prompted trials. Both auditory and visual warning cues shortened the reaction time for the Go trials. The warning cues activated the right-lateralized parieto-frontal top-down attentional network, and motor cortical areas including the pre-supplementary motor area (pre-SMA), the bilateral dorsal premotor cortex, and the left primary motor cortex (M1). The warning-related activation of the pre-SMA matched the difference between its activation by Go-with-warning and by Go-without-warning. Thus, the pre-SMA was primed by the warning cue. The same pre-SMA priming effect was observed for the No-Go cue-related activation, consistent with its role in movement preparation and selection. Similar but less prominent Go cue-related priming was observed in the M1. Thus, the warning effect represents the pre-potentiation of the motor control pathway by the top-down attentional system, from the selection and preparation of the movement to its execution.

Pigment epithelium-derived factor (PEDF) administration inhibits occlusive thrombus formation in rats: a possible participation of reduced intraplatelet PEDF in thrombosis of acute coronary syndromes.

OBJECTIVES: Although remarkable therapeutic advances in the treatment of acute coronary syndromes (ACS) have been made with anti-platelet therapy, the therapeutic options may be limited by considerable side effects. Pigment epithelium-derived factor (PEDF) has anti-oxidative properties and may play a protective role against atherosclerosis. In this study, we investigated whether PEDF prevented occlusive thrombus formation in rats. METHODS AND RESULTS: Occlusive thrombus formation was induced by treating rats with ligation and cuff placement at the left common carotid artery. Intravenous injection of PEDF dose-dependently inhibited thrombus formation and blocked the increase in immunoreactivity of P-selectin, a marker of platelet activation, NADPH oxidase activity and superoxide generation in thrombi. In vitro, PEDF significantly decreased collagen-induced reactive oxygen species generation in platelets and subsequently suppressed the platelet activation and aggregation. Plasma and intraplatelet levels of PEDF in the coronary circulation in patients with ACS were significantly lower than those in age- and gender-matched controls without coronary artery disease. CONCLUSIONS: These results demonstrated that PEDF administration could inhibit occlusive thrombus formation by blocking the platelet activation and aggregation through its anti-oxidative properties. Our present study suggests that pharmacological up-regulation or substitution of PEDF may offer a promising strategy for the treatment of arterial thrombosis.

Pigment-epithelium-derived factor suppresses expression of receptor for advanced glycation end products in the eye of diabetic rats.

The interaction of advanced glycation end products (AGEs) and their receptor (RAGE) elicits inflammatory and proliferative responses in retinal vascular wall cells, thereby being involved in the pathogenesis of diabetic retinopathy. Recently, pigment-epithelium-derived factor (PEDF) has also been shown to play a role in diabetic retinopathy. However, the effects of PEDF on RAGE gene expression remain to be elucidated. Therefore, we investigated here whether PEDF could prevent diabetes- or AGE-induced RAGE gene expression and the way that it might achieve this effect. Administration of PEDF or pyridoxal phosphate, an AGE inhibitor, suppressed RAGE gene expression in the eye of streptozotocin-induced diabetic rats. Further, intravenous injection of AGEs to normal rats increased RAGE gene expression, which was also blocked by PEDF. In vitro, PEDF or an antioxidant N-acetylcysteine blocked the AGE-induced RAGE gene induction in microvascular endothelial cells. In addition, PEDF completely inhibited superoxide generation and NF-kappaB activation in AGE-exposed endothelial cells. These results demonstrated that PEDF could inhibit diabetes- or AGE-induced RAGE gene expression by blocking the superoxide-mediated NF-kappaB activation. Our present study suggests that pharmacological upregulation or substitution of PEDF may play a protective role against diabetic retinopathy by attenuating the deleterious effect of AGEs.