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Mitochondrial damage in the trabecular meshwork occurs only in primary open-angle glaucoma and in pseudoexfoliative glaucoma.
No full textBackgroundOpen-angle glaucoma appears to be induced by the malfunction of the trabecular meshwork cells due to injury induced by oxidative damage and mitochondrial impairment. Here, we report that, in fact, we have detected mitochondrial damage only in primary open-angle glaucoma and pseudo-exfoliation glaucoma, among several glaucoma types compared.Methodology/principal findingsMitochondrial damage was evaluated by analyzing the common mitochondrial DNA deletion by real-time PCR in trabecular meshwork specimens collected at surgery from glaucomatous patients and controls. Glaucomatous patients included 38 patients affected by various glaucoma types: primary open-angle, pigmented, juvenile, congenital, pseudoexfoliative, acute, neovascular, and chronic closed-angle glaucoma. As control samples, we used 16 specimens collected from glaucoma-free corneal donors. Only primary open-angle glaucoma (3.0-fold) and pseudoexfoliative glaucoma (6.3-fold) showed significant increases in the amount of mitochondrial DNA deletion. In all other cases, deletion was similar to controls.Conclusions/significancedespite the fact that the trabecular meshwork is the most important tissue in the physiopathology of aqueous humor outflow in all glaucoma types, the present study provides new information regarding basic physiopathology of this tissue: only in primary open-angle and pseudoexfoliative glaucomas oxidative damage arising from mitochondrial failure play a role in the functional decay of trabecular meshwork
Modulation of microRNA expression by budesonide, phenethyl isothiocyanate, and cigarette smoke in mouse liver and lung.
No full textAlthough microRNAs (miRNA) have extensively been investigated in cancer research, less attention has been paid to their regulation by carcinogens and/or protective factors in early stages of the carcinogenesis process. The present study was designed to evaluate the modulation of mRNA expression as related to exposure of neonatal mice to environmental cigarette smoke (ECS) and to treatment with chemopreventive agents. Exposure to ECS started immediately after birth and for 2 weeks after weaning. Thereafter, groups of mice received daily either budesonide (BUD) or phenethyl isothiocyanate (PEITC) with the diet. The expression of 576 miRNAs was evaluated by miRNA microarray in liver and lung. In sham-exposed mice, the expression of miRNAs tended to be higher in liver than in lung. ECS downregulated the expression of a number of miRNAs in lung, whereas mixed alterations were observed in liver. PEITC and BUD did not substantially affect the physiological situation in lung, whereas both agents caused intense variations in liver, reflecting the occurrence of damage mechanisms, such as inflammation, DNA and protein damage, cellular stress, proliferation and apoptosis. PEITC and BUD protected the lung from ECS-induced alterations of miRNA expression but exhibited some adverse effects in liver. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Proteome Alterations in Primary Open Angle Glaucoma Aqueous Humor
No full textAs the only nourishment and scavenging source for most of the anterior and posterior chamber tissues in the eye, the aqueous humor represents one of the target for glaucoma. The aim of this study is to investigate the yet unexplored relationship between aqueous humor protein content and open-angle glaucoma (POAG) pathogenesis. Aqueous humor was collected from 10 POAG patients (cases) and 14 senile cataract patients (controls), matched for age and gender, undergoing surgery for trabeculectomy and cataract, respectively. Protein samples were cyanine-labeled and hybridized with antibody microarrays. Microarray signals were revealed by laser scanner, quantified, and compared by statistical analyses. Total protein amounts were not significantly different in patients versus controls. Conversely, a proteome cluster significantly modified in patients as compared to controls was identified as highly predictive for disease status. Selected proteins underwent dramatic variation, which was correlated to pathogenetic events characterizing POAG, including oxidative damage, mitochondrial damage, neural degeneration, and apoptosis. The results obtained indicate that proteomic analysis of aqueous humor is a new tool for POAG diagnosis in the case of otherwise uncertain disease recognition. Furthermore, this study allows a better understanding of mechanisms involved in the pathogenesis of POAG, the main cause of irreversible blindness worldwide. © 2010 American Chemical Society
Alterations of gene expression in skin and lung of mice exposed to light and cigarette smoke
No full textWe previously showed that sunlight-mimicking light induces genotoxic damage not only in skin but also even in lung, bone marrow, and peripheral blood of hairless mice. Moreover, light and smoke acted synergically in the respiratory tract. To clarify the mechanisms involved, we investigated by cDNA-arrays the expression of 746 toxicologically relevant genes in skin and lungs of mice exposed for 28 days to light and/or environmental cigarette smoke. Glutathione-S-transferase-Pi and catalase were overexpressed in the lungs of mice exposed to light only. Moreover, the light induced in skin the expression of genes involved in carcinogenesis, photoaging, and production of genotoxic and oxidizing derivatives traveling at a distance. Smoke induced the expression of multiple genes in both skin and lung, which reflect adaptive responses and mechanisms related to cancer and, possibly, to emphysema and stroke. As shown in mice exposed to both light and smoke, the light tended to increase smoke-induced gene expression in lungs, while smoke tended to attenuate light-induced gene expression in skin. The oral administration of the nonsteroidal anti-inflammatory drug sulindac inhibited the light-induced overexpression of cyclooxygenase-2 and oxidative stress-related genes in skin, and down-regulated smoke-induced genes involved in oxidative stress, removal of damaged proteins, inflammation, and immune response in lung. These results provide a mechanistic insight explaining the systemic alterations induced by both light and smoke in mouse skin and lungs
Sensitivity of Ocular Anterior Chamber Tissues to Oxidative Damage and Its Relevance to the Pathogenesis of Glaucoma
No full textPURPOSE. The anterior chamber of the eye is a highly specialized structure delimited by the cornea, lens, and iris. It contains the aqueous humor, secreted by the ciliary body and drained by the trabecular meshwork. Alteration of aqueous humor homeostasis plays a major role in the pathogenesis of glaucoma. The trabecular meshwork is the target tissue of glaucoma in the anterior chamber, and the development and progression of glaucoma are accompanied by accumulation of oxidative damage in this tissue. This study was conducted to comparatively evaluate the sensitivity to oxidative stress of anterior chamber tissues including the cornea, iris, and trabecular meshwork. METHODS. Cornea, iris, and trabecular meshwork fragments collected from six cornea donors were either left untreated or treated with hydrogen peroxide. Oxidative damage was determined by evaluating nucleotide oxidative modifications (8-hydroxy-2'-deoxyguanosine) and apurinic alkali-fragile sites by capillary electrophoresis. RESULTS. The results indicated that the basal level of oxidative nucleotide modifications was higher in the cornea than in the iris and trabecular meshwork. The trabecular meshwork was the most sensitive tissue to oxidative damage, as after exposure to hydrogen peroxide both markers of oxidative damage dramatically increased in the trabecular meshwork but not in the cornea and iris. CONCLUSIONS. Because the cornea and iris are directly exposed to light, they possess antioxidant defense mechanisms that are not activated in the trabecular meshwork. The peculiar sensitivity of the trabecular meshwork to oxidative stress is consistent with the damage selectively induced in it, triggering glaucoma's pathogenic cascade. © Association for Research in Vision and Ophthalmology
Birth-related genomic and transcripional changes in mouse lung. Modulation by transplacental N-acetylcysteine.
No full textGenomic and transcriptional alterations in mouse fetus liver after transplacental exposure to cigarette smoke
No full textPharmacological modulation of genome and proteome alterations in mice treated with the endocrine disruptor bisphenol A
No full textSmoke-induced microRNA and related proteome alterations. Modulation by chemopreventive agents.
No full textDysregulation of microRNAs (miRNAs) has important consequences on gene and protein expression since a single miRNA targets a number of genes simultaneously. This article provides a review of published data and ongoing studies regarding the effects of cigarette smoke (CS), either mainstream (MCS) or environmental (ECS), on the expression of miRNAs and related proteins. The results generated in mice, rats, and humans provided evidence that exposure to CS results in an intense dysregulation of miRNA expression in the respiratory tract, which is mainly oriented in the sense of downregulation. In parallel, there was an upregulation of proteins targeted by the downregulated miRNAs. These trends reflect an attempt to defend the respiratory tract by means of antioxidant mechanisms, detoxification of carcinogens, DNA repair, anti-inflammatory pathways, apoptosis, etc. However, a long-lasting exposure to CS causes irreversible miRNA alterations that activate carcinogenic mechanisms, such as modulation of oncogenes and oncosuppressor genes, cell proliferation, recruitment of undifferentiated stem cells, inflammation, inhibition of intercellular communications, angiogenesis, invasion, and metastasis. The miRNA alterations induced by CS in the lung of mice and rats are similar to those observed in the human respiratory tract. Since a number of miRNAs that are modulated by CS and/or chemopreventive agents are subjected to single nucleotide polymorphisms in humans, they can be evaluated according to toxicogenomic/pharmacogenomics approaches. A variety of cancer chemopreventive agents tested in our laboratory modulated both baseline and CS-related miRNA and proteome alterations, thus contributing to evaluate both safety and efficacy of dietary and pharmacological agents
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