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Sacca S.C.,Ophthalmology Unit | Izzotti A.,University of Genoa
Cellular and Molecular Life Sciences | Year: 2014

Primary open-angle glaucoma is a multifactorial disease that affects the retinal ganglion cells, but currently its therapy is to lower the eye pressure. This indicates a definite involvement of the trabecular meshwork, key region in the pathogenesis of glaucoma. This is the first target of glaucoma, and its functional complexity is a real challenge to search. Its functions are those to allow the outflow of aqueous humor and not the reflux. This article describes the morphological and functional changes that happen in anterior chamber. The "primus movens" is oxidative stress that affects trabecular meshwork, particularly its endothelial cells. In these develops a real mitochondriopaty. This leads to functional impotence, the trabecular meshwork altering both motility and cytoarchitecture. Its cells die by apoptosis, losing barrier functions and altering the aqueous humor outflow. All the morphological alterations occur that can be observed under a microscope. Intraocular pressure rises and the malfunctioning trabecular meshwork endotelial cells express proteins that completely alter the aqueous humor. This is a liquid whose functional proteomics complies with the conditions of the trabecular meshwork. Indeed, in glaucoma, it is possible detect the presence of proteins which testify to what occurs in the anterior chamber. There are six classes of proteins which confirm the vascular endothelium nature of the anterior chamber and are the result of the morphofunctional trabecular meshwork decay. It is possible that, all or in part, these proteins can be used as a signal to the posterior pole. © 2013 Springer Basel. Source


Sacca S.C.,Ophthalmology Unit | Roszkowska A.M.,Messina University | Izzotti A.,University of Genoa
Mutation Research - Reviews in Mutation Research | Year: 2013

The human eye is constantly exposed to sunlight and artificial lighting. Exogenous sources of reactive oxygen species (ROS) such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins contribute to oxidative damage in ocular tissues. Long-term exposure to these insults places the aging eye at considerable risk for pathological consequences of oxidative stress. Furthermore, in eye tissues, mitochondria are an important endogenous source of ROS. Over time, all ocular structures, from the tear film to the retina, undergo oxidative stress, and therefore, the antioxidant defenses of each tissue assume the role of a safeguard against degenerative ocular pathologies. The ocular surface and cornea protect the other ocular tissues and are significantly exposed to oxidative stress of environmental origin. Overwhelming of antioxidant defenses in these tissues clinically manifests as pathologies including pterygium, corneal dystrophies, and endothelial Fuch's dystrophy. The crystalline lens is highly susceptible to oxidative damage in aging because its cells and their intracellular proteins are not turned over or replaced, thus providing the basis for cataractogenesis. The trabecular meshwork, which is the anterior chamber tissue devoted to aqueous humor drainage, has a particular susceptibility to mitochondrial oxidative injury that affects its endothelium and leads to an intraocular pressure increase that marks the beginning of glaucoma. Photo-oxidative stress can cause acute or chronic retinal damage. The pathogenesis of age-related macular degeneration involves oxidative stress and death of the retinal pigment epithelium followed by death of the overlying photoreceptors. Accordingly, converging evidence indicates that mutagenic mechanisms of environmental and endogenous sources play a fundamental pathogenic role in degenerative eye diseases. © 2013 Elsevier B.V. Source


Sacca S.C.,Ophthalmology Unit | Centofanti M.,University of Rome Tor Vergata | Izzotti A.,University of Genoa
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. The aim of this study was to investigate the expression level of several biomarkers in the in the aqueous humor of 14 patients with primary open angle glaucoma who underwent glaucoma surgery, and 11 nonglaucomatous normals who underwent cataract extraction surgery. METHODS. The aqueous humor proteome of 25 patients was analyzed using an antibody microarray. Fourteen patients with uncontrolled intraocular pressure-despite profound therapeutic interventions-who underwent filtering procedures and 11 control subjects who underwent surgery for senile cataracts were included in the present study. Protein expression was evaluated using Cy3/Cy5 labeling, column purification, and hybridization on antibody-spotted glass microarrays. Fluorescent signals were detected by fluorescence laser scanning. RESULTS. The levels of 13 proteins were significantly increased in the aqueous humor of glaucomatous patients compared with expression levels in healthy controls. One of the 13 proteins (ELAM 1) was involved in inflammation. Two of these proteins (apolipoprotein B and E) were involved in the delivery of cholesterol to cells. Five of the 13 proteins (myotrophin, myoblast determination protein 1, myogenin, vasodilatorstimulated phosphoprotein, and ankyrin-2) were involved in muscle cell differentiation and function. Three proteins (heat shock 60 kilodaltons (kDa) and 90 kDa proteins, and ubiquitin fusion degradation 1-like) were involved in stress response and the removal of damaged proteins; and two proteins (phospholipase C β and γ) were involved in signal transduction and neural development. CONCLUSIONS. The expressions of these proteins in the aqueous humor of glaucomatous patients reflect the damage occurring in anterior chamber endothelia, mainly including the trabecular meshwork, which is the main structure of this ocular segment injured by glaucoma. © 2012 The Association for Research in Vision and Ophthalmology, Inc. Source


Sacca S.C.,Ophthalmology Unit | Pulliero A.,University of Genoa | Izzotti A.,University of Genoa | Izzotti A.,Italian National Cancer Institute
Journal of Cellular Physiology | Year: 2015

Primary open angle glaucoma is a multi-tissue disease that targets, in an ascending order, the trabecular meshwork, the optic nerve head, the lateral geniculate nuclei, and the visual cortex. Oxidative stress and vascular damage play major roles in triggering apoptotic cell loss in these tissues. Molecular alterations occurring in the ocular anterior chamber during the early course of glaucoma trigger this cell loss. These molecular events are mainly of endogenous origin and related to the long-term accumulation of oxidative damages arising from mitochondrial failure and endothelial dysfunction. This situation results in decreased antioxidant defences in aqueous humour and apoptosis activation in trabecular meshwork cells as triggered by severe mitochondrial damage altering tissue function and integrity. The presence of neural proteins in glaucomatous aqueous humour indicate that a molecular interconnection exists between the anterior and the posterior chamber tissues. Trabecular meshwork and lamina cribrosa share a common neuro-ectodermal embryological, which contribute to explain the interconnection between anterior and the posterior chamber during glaucoma pathogenesis. During glaucoma, proteins deriving from the damage occurring in endothelial trabecular meshwork cells are released into aqueous humour. Accordingly, aqueous humour composition is characterised in glaucomatous patients by the presence of proteins deriving from apoptosis activation, mitochondrial damage, loss of intercellular connections, antioxidant decrease. Many questions remain unanswered, but molecular events illuminate TM damage and indicate that trabecular cell protection plays a role in the treatment and prevention of glaucoma. © 2014 Wiley Periodicals, Inc., A Wiley Company. Source


Izzotti A.,University of Genoa | Sacca S.C.,Ophthalmology Unit | Longobardi M.,University of Genoa | Cartiglia C.,University of Genoa
Archives of Ophthalmology | Year: 2010

Objectives: To analyze the frequency of mitochondrial DNA (mtDNA) damage in patients with primary open-angle glaucoma. Oxidative damage plays a major role in glaucoma pathogenesis. Since no environmental risk factor for glaucoma is recognized, we focused our attention on mitochondria, the main endogenous source of reactive oxygen species. Methods: Mitochondrial damage was evaluated analyzing a common mtDNA deletion by real-time polymerase chain reaction in trabecular meshwork collected at surgery from 79 patients with primary open-angle glaucoma and 156 unaffected matched controls. In the same samples, polymorphisms of genes encoding for antioxidant defenses (GSTM1), repair of oxidative DNA damage (OGG1), and apoptosis (FAS) were tested. Results: Mitochondrial DNA deletion was dramatically increased (5.32-fold; P=.01) in trabecular meshwork of patients with glaucoma vs controls. This finding was paralleled by a decrease in the number of mitochondria per cell (4.83-fold; P<.001) and by cell loss (16.36-fold; P<.01). Patients with glaucoma bearing the GSTM1-null genotype showed increased amounts of mtDNA deletion and a decreased number of mitochondria per cell as compared with GSTM1-positive subjects. Patients bearing a FAS homozygous mutation showed only a decreased number of mitochondria per cell. Conclusions: Obtained results indicate that mitochondrion is targeted by the glaucomatous pathogenic processes. Some subjects bearing adverse genetic assets are more susceptible to this event. Clinical Relevance: Oxidative damage to the trabecular meshwork exerts a pathogenic role in glaucoma inducing mitochondrial damage and triggering apoptosis and cell loss. This issue may be useful to develop new glaucoma molecular biomarkers and to identify highrisk subjects. ©2010 American Medical Association. Source

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