Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-recoverin autoantibodies have been associated with cancer-associated retinopathy (CAR), a paraneoplastic blinding disease. Those antibodies have been shown to induce apoptotic death of photoreceptor cells. The objective was to ascertain the mechanisms of retinal death induced by anti-recoverin antibody in vitro by examining the apoptotic pathway involved in retinal cell death. Internalization of anti-recoverin antibody or its Fab fragments by retinal cells mediated by endocytosis lead to cytotoxicity. Antibody cellular translocation induced the increase of bcl-x(s) and bax and the decrease in the bcl-x(L) protein. We detected the release of cytochrome c and down-regulation of the apaf-1 protein. This correlated with the sequential activation of caspase 9 and caspase 3, as well as the degradation of the caspase substrate PARP and the fragmentation of DNA. Our data show that anti-recoverin antibodies are inducers of apoptosis through the mitochondrial pathway involving caspases 9 and 3. We propose that a similar mechanism may be in place in patients with CAR syndrome where high levels of circulating antibodies have been associated with retinal degeneration.
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PMID:Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway. 1241 36

Apoptosis of retinal endothelial cells and pericytes is postulated to contribute to the development of retinopathy in diabetes. The goal of this study is to investigate diabetes-induced activation of retinal caspase-3, an apoptosis executer enzyme, in retina, and examine the effects of antioxidants on the activation. Caspase-3 activation was determined in the retina of alloxan diabetic rats (2-14 months duration) and in the isolated retinal capillary cells (endothelial cells and pericytes) by measuring cleavage of caspase-3 specific fluorescent substrate, and cleavage of caspase-3 holoenzyme and poly (ADP ribosyl) polymerase. Effect of antioxidants on the activation of caspase-3 was determined by feeding a group of diabetic rats diet supplemented with a comprehensive mixture of antioxidants, including Trolox, alpha-tocopherol, N-acetyl cysteine, ascorbic acid, beta-carotene and selenium for 2-14 months, and also under in vitro conditions by incubating isolated retinal capillary cells with antioxidants with wide range of actions. Caspase-3 was activated in the rat retina at 14 months of diabetes (P < 0.05 vs. normal), but not at 2 months of diabetes, and administration of antioxidants for the entire duration inhibited this activation. In the isolated retinal capillary cells incubated in 25 mM glucose medium, caspase-3 activity was increased by 50% compared to the cells incubated in 5 mM glucose (P < 0.02), and antioxidants or caspase-3 inhibitor inhibited this increase. Our results suggest that increased oxidative stress in diabetes is involved in the activation of retinal caspase-3 and apoptosis of endothelial cells and pericytes. Antioxidants might be inhibiting the development of diabetic retinopathy by inhibiting microvascular apoptosis.
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PMID:Diabetes-induced activation of caspase-3 in retina: effect of antioxidant therapy. 1244 25

Hyperoxia exposure induces capillary endothelial cell apoptosis in the developing retina, leading to vaso-obliteration followed by proliferative retinopathy. Previous in vivo studies have shown that endothelial nitric oxide synthase (NOS3) and peroxynitrite are important mediators of the vaso-obliteration. Now we have investigated the relationship between hyperoxia, NOS3, peroxynitrite, and endothelial cell apoptosis by in vitro experiments using bovine retinal endothelial cells (BREC). We found that BREC exposed to 40% oxygen (hyperoxia) for 48 h underwent apoptosis associated with activation of caspase-3 and cleavage of the caspase substrate poly(ADP-ribose) polymerase. Hyperoxia-induced apoptosis was associated with increased formation of nitric oxide, peroxynitrite, and superoxide anion and was blocked by treatment with uric acid, nitro-L-arginine methyl ester, or superoxide dismutase. Analyses of the phosphatidylinositol 3-kinase/Akt kinase survival pathway in cells directly treated with peroxynitrite revealed inhibition of VEGF- and basic FGF-induced activation of Akt kinase. These results suggest that hyperoxia-induced formation of peroxynitrite induces BREC apoptosis by crippling key survival pathways and that blocking peroxynitrite formation prevents apoptosis. These data may have important clinical implications for infants at risk of retinopathy of prematurity.
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PMID:Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite. 1273 39

Circulating antibodies specific to retinal proteins have been associated with retinal dysfunction in patients with retinopathy. Anti-recoverin antibodies found in patients with cancer-associated retinopathy (CAR) represent a unique model to study the relationship between retinal degeneration and autoimmunity. A body of evidence from in vitro and in vivo studies indicates that anti-recoverin autoantibodies are cytotoxic to retinal cells and induce apoptotic death of retinal photoreceptor cells, which leads to the degeneration of the photoreceptor cell layer. Similar to anti-recoverin autoantibodies, antibodies with other retinal specificities induce their target retinal cell death by activating a caspase 3-dependent apoptotic pathway. Thus, autoantibody-induced apoptosis may be a common pathway that leads to retinal death and blindness.
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PMID:Autoantibody-induced apoptosis as a possible mechanism of autoimmune retinopathy. 1284 60

Autoantibodies against recoverin are found in the sera of patients with cancer-associated retinopathy syndrome, a paraneoplastic disease associated with retinal degeneration. We have previously shown that anti-recoverin autoantibodies induced photoreceptor apoptotic cell death after injection into the vitreous of Lewis rats. Ciliary neurotrophic factor (CNTF) has been shown to promote the survival of a number of neuronal cell types, including photoreceptors. In this study, we examined whether an adeno-associated virus (AAV)-mediated delivery of gene encoding the human CNTF protected photoreceptor cells from anti-recoverin antibody-induced death. One month after subretinal injection of the AAV-CNTF gene into one eye and a control vector into the other eye, an anti-recoverin antibody was injected to induce retinal cell death in Lewis rats. Subretinal administration of the virus led to an efficient transduction of photoreceptors, as indicated by immunostaining of retinas with anti-CNTF. Histological examination of the corresponding retinas showed that photoreceptor cells were significantly protected from apoptotic death in the CNTF-treated eyes. CNTF treatment of the retinas resulted in a time-dependent activation of STAT 3. The present study shows that an AAV-mediated delivery of CNTF may protect photoreceptors from antibody-induced cell death through the activation of STAT3 and the suppression of caspase 3 activity, a key caspase leading to apoptosis. Thus, CNTF may be a useful treatment for human antibody-mediated retinal degeneration.
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PMID:Anti-apoptotic effects of CNTF gene transfer on photoreceptor degeneration in experimental antibody-induced retinopathy. 1293 81

Retinal degeneration is an early and progressive event in many forms of neuronal ceroid lipofuscinoses (NCLs), a heterogeneous group of neurodegenerative disorders with unknown pathogenesis. We here used the mutant motor neuron degeneration (mnd) mouse, a late-infantile NCL variant, to investigate the retinal oxidative state and apoptotic cell death as a function of age and sex. Total superoxide dismutase (SOD) activities and thiobarbituric acid-reactive substance (TBARS) levels revealed progressive increases in retinal oxyradicals and lipid peroxides of mnd mice of both sexes. Female mnd retinas showed a higher oxidation rate and consistently exhibited the 4-hydroxy-2-nonenal (4-HNE)-adducts staining and advanced histopathologic profile when compared to male mnd retinas matched for age. In situ DNA fragmentation (TUNEL staining) appeared in the outer nuclear layer (ONL) as early as 1 month of age. At 4 months, there were more intense and numerous TUNEL-positive cells in the same layer and in the inner nuclear (INL) and ganglion cell (GCL) layers; whereas at 8 months TUNEL staining was restricted to a few scattered cells in the INL and GCL, when a severe retinal cell loss had occurred. Caspase-3 activation confirmed apoptotic demise and its processing turned out to be higher in mnd females than males. These results demonstrate the involvement of oxidation and apoptotic processes in mnd mouse retinopathy and highlight sex-related differences in retinal vulnerability to oxidative stress and damage.
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PMID:Retinal oxidation, apoptosis and age- and sex-differences in the mnd mutant mouse, a model of neuronal ceroid lipofuscinosis. 1521 5

Autoantibodies against alpha-enolase are often associated with visual loss in patients with autoimmune retinopathy. Anti-recoverin autoantibodies have been the most extensively studied for their pathologic association with cancer-associated retinopathy (CAR). It has been shown that anti-recoverin antibodies penetrate retinal layers corresponding to the cellular location of recoverin and cause the death of photoreceptors and bipolar cells. However, the pathogenic effects of anti-alpha-enolase antibodies have not been studied. In this study, we tested the labeling and apoptotic effects of such autoantibodies on retinal cells. Serum antibodies against alpha-enolase from patients with autoimmune retinopathy were tested ex vivo and in vivo in Sprague-Dawley rats. Autoantibodies to alpha-enolase specifically labeled the retinal ganglion cells and inner nuclear layer cells. Using ex vivo experiments and intravitreal injections, we observed that antibodies were capable of penetrating retinal tissue to target ganglion cell and inner nuclear layers and, consequently, were able to induce cell death through an apoptotic process. The apoptotic nuclei detected by a DNA fragmentation assay and caspase 3-positive cells were co-localized in the ganglion cell layer and inner nuclear layer. The results showed that antibodies against alpha-enolase target antigens in these layers and induce the apoptotic death of sensitive cells. Rat retinal explants and the intravitreal injection of antibodies provide us with a good model to identify antibody pathogenic targets in the retina. Such identification may help explain the complex of clinical symptoms for autoimmune retinopathy mediated by autoantibody and may help guide treatment strategies.
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PMID:Cellular targets of anti-alpha-enolase autoantibodies of patients with autoimmune retinopathy. 1532 34

Advanced glycation end-products (AGEs) are considered to play an important role in the development of retinopathy in diabetes, and are shown to induce retinal vascular changes resembling that of diabetic retinopathy. We have shown that apoptosis of retinal capillary cells is accelerated in diabetes. The aim of this study is to investigate the role of AGEs in accelerated retinal capillary cell death in in vitro conditions, and to identify the possible mechanism involved. Bovine retinal endothelial cells and pericytes were incubated in the presence of 5 microM AGE-bovine serum albumin (AGE-BSA) or untreated control BSA (BSA) for up to five days. The cell death was determined by performing ELISA for cytoplasmic histone-associated DNA fragments and by measuring the activity of caspase-3. Incubation of endothelial cells or pericytes with AGE-BSA increased oxidative stress and NO by 60%, and in the same cells nuclear transcriptional factor (NF-kB) was also activated by over 60%. AGE-BSA induced their apoptosis by 55%, and activated caspase-3 by about 50% compared to the cells incubated with unmodified BSA. Co-addition of AGE-BSA and antioxidants (N-acetyl cysteine or alpha-lipoic acid) inhibited oxidative stress, nitrotyrosine formation, NF-kB activation and capillary cell apoptosis. These data strongly suggest that increased AGE in diabetes could play an important role in retinal capillary apoptosis and that oxidative stress is involved in this process. Inhibition of AGEs in the retinal capillary cells could prevent their apoptosis, and ultimately, the development of retinopathy in diabetes.
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PMID:Effect of advanced glycation end products on accelerated apoptosis of retinal capillary cells under in vitro conditions. 1560 33

Hyperglycemia is one of the major underlying factors in the development of retinopathy in diabetes. Retinal microvascular cells undergo accelerated apoptosis before other histopathological changes are detectable in diabetes. We examined the effect of re-institution of good metabolic control (GC) on the activation of retinal apoptosis executor enzyme, caspase-3, and nuclear transcriptional factor NF-kB. In streptozotocin diabetic rats, two or six months of poor metabolic control (PC) with glycated hemoglobin >11.0% was followed by seven additional months of GC (glycated hemoglobin <5.5%). Caspase-3 activity in retina was measured by the cleavage of its substrate, the expression of active 17 kD subunit, and cleavage of poly(ADP ribosyl) polymerase. NF-kB activation was determined by electrophoretic shift assay and by western blots for P65 subunit. Caspase-3 activity in diabetic rats kept in PC for 13 months was 175% that in normal rats. Re-institution of GC after two months of PC partially normalized the hyperglycemia-induced activation of caspase-3 (to 140% of normal values) while re-institution of GC after six months of PC had no significant effect on the activation of caspase-3 NF-kB activity was 2.5-fold higher in diabetic rats kept in PC than in normal rats. Re-institution of GC after 2 months of PC partially reversed this increase (X-fold over normal), but GC after 6 months of PC had no effect. Initiation of GC soon after induction of diabetes in rats prevented activation of retinal caspase-3 and NF-kB. These results suggest that the process of activation of apoptosis execution enzyme and NF-kB in retina that starts before appearance of histopathological changes is not easily reversed by re-institution of GC. Characterization of the abnormalities responsible for the resistance of retinopathy to halt after re-institution of GC will help identify potential therapies for inhibition of progression of diabetic retinopathy.
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PMID:Re-institution of good metabolic control in diabetic rats and activation of caspase-3 and nuclear transcriptional factor (NF-kappaB) in the retina. 1566 Feb 3

Oxidative stress is increased in the retina in diabetes; the levels of oxidatively modified DNA and nitrosylated proteins are elevated, and antioxidant defense enzymes are impaired. The levels of superoxides are elevated in the retina, and the mitochondria become dysfunctional with proapoptotic protein, Bax, translocating from the cytosol into the mitochondria, and cytochrome c leaking out from the mitochondria. This is accompanied by increased retinal capillary cell apoptosis, and the formation of acellular capillaries and pericyte ghosts, the early signs of retinopathy in animal models of diabetic retinopathy. Inhibition of superoxides inhibits glucose -induced mitochondrial dysfunction, activation of caspase-3, and cell death in retinal capillary cells. In animal models, long-term administration of lipoic acid or other antioxidants inhibits the development of diabetic retinopathy via inhibition of accumulation of oxidatively modified DNA and nitrotyrosine and capillary cell apoptosis in the retina. Understanding the role of mitochondria in the development of retinopathy in diabetes should help identify therapies that can neutralize superoxides and inhibit their dysfunction and, ultimately, the development of retinopathy.
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PMID:Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. 1635 21


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