Neuroprotective and Anti-Inflammatory Effects of a Hydrophilic Saffron Extract in a Model of Glaucoma.

Glaucoma is a neurodegenerative disease characterized by the loss of retinal ganglion cells (RGCs). An increase in the intraocular pressure is the principal risk factor for such loss, but controlling this pressure does not always prevent glaucomatous damage. Activation of immune cells resident in the retina (microglia) may contribute to RGC death. Thus, a substance with anti-inflammatory activity may protect against RGC degeneration. This study investigated the neuroprotective and anti-inflammatory effects of a hydrophilic saffron extract standardized to 3% crocin content in a mouse model of unilateral, laser-induced ocular hypertension (OHT). Treatment with saffron extract decreased microglion numbers and morphological signs of their activation, including soma size and process retraction, both in OHT and in contralateral eyes. Saffron extract treatment also partially reversed OHT-induced down-regulation of P2RY12. In addition, the extract prevented retinal ganglion cell death in OHT eyes. Oral administration of saffron extract was able to decrease the neuroinflammation associated with increased intraocular pressure, preventing retinal ganglion cell death. Our findings indicate that saffron extract may exert a protective effect in glaucomatous pathology.

A Multi-Locus Genetic Risk Score for Primary Open-Angle Glaucoma (POAG) Variants Is Associated with POAG Risk in a Mediterranean Population: Inverse Correlations with Plasma Vitamin C and E Concentrations.

Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. The genetics of POAG are complex, and population-specific effects have been reported. Although many polymorphisms associated with POAG risk have been reported, few studies have analyzed their additive effects. We investigated, in a southern European Mediterranean population, the association between relevant POAG polymorphisms, identified by initial genome-wide association studies (GWASs) and POAG risk, both separately and as an aggregated multi-locus genetic risk score (GRS). Also, bearing in mind that oxidative stress is a factor increasingly recognized in the pathogenesis of POAG, we analyzed the potential association of the GRS with plasma concentrations of antioxidant vitamins (C and E). We carried out a case-control study including 391 POAG cases and 383 healthy controls, and analyzed four genetic polymorphisms (rs4656461-TMCO1, rs4236601-CAV1/CAV2, rs2157719-CDKN2B-AS1 and rs3088440-CDKN2A). An unweighted GRS including the four non-linked polymorphisms was constructed. A strong association between the GRS and POAG risk was found. When three categories of the GRS were considered, subjects in the top category of the GRS were 2.92 (95% confidence interval (CI): 1.79-4.77) times more likely to have POAG compared with participants in the bottom category (p < 0.001). Moreover, the GRS was inversely correlated with plasma vitamin C (p = 0.002) and vitamin E (p = 0.001) concentrations, even after additional adjustment for POAG status. In conclusion, we have found a strong association between the GRS and POAG risk in this Mediterranean population. While the additional correlation found between GRS and low levels of vitamins C and E does not indicated a causal relationship, it does suggest the need for new and deeper research into the effects of oxidative stress as a potential mechanism for those associations.

Genetic polymorphism related to exfoliative glaucoma is also associated with primary open-angle glaucoma risk.

BACKGROUND: To investigate the possible association of the rs2165241 polymorphism (C > T) in LOXL1 gene with the risk of primary open-angle glaucoma in a Mediterranean population. METHODS: The analysis of genetic polymorphisms was performed by standard TaqMan allelic discrimination technique, using a 7900HT Sequence Detection System (Applied Biosystems). RESULTS: In a recessive genetic model, the T allele of the rs2165241 polymorphism was significantly associated with the risk of primary open-angle glaucoma (TT vs. CC: odds ratios = 2.19, 95% confidence interval = [1.33-3.62]). After multivariate logistic regression model adjusted by age and weight, the magnitude of the association decreased but remained statistically significant (TT vs. CC: odds ratios = 2.07, 95% confidence interval = [1.20-3.57]). CONCLUSION: This polymorphism seems to be associated with high risk for primary open-angle glaucoma in a Mediterranean population.

Effects of polymorphisms in vitamin E-, vitamin C-, and glutathione peroxidase-related genes on serum biomarkers and associations with glaucoma.

PURPOSE: To study the association of selected polymorphism in genes related to vitamin E, vitamin C, and glutathione peroxidase with these biomarkers and primary open-angle glaucoma (POAG) risk. METHODS: A case-control study matched for age, sex, and bodyweight was undertaken. Two hundred fifty POAG cases and 250 controls were recruited from a Mediterranean population. Plasma concentrations of vitamin C, vitamin E, and glutathione peroxidase (GPx) activity were measured. We analyzed the polymorphisms rs1279683 in the Na(+)-dependent L-ascorbic acid transporter 2 (SLC23A2) gene, rs6994076 in the tocopherol alpha transfer protein (TTPA) gene, rs737723 in the tocopherol-associated protein (SEC14L2/TAP) gene, and rs757228 in the glutathione peroxidase 4 (GPX4) gene. We also analyzed expression of the SLC23A2 gene in a subsample. RESULTS: We found a novel association between the rs737723 polymorphism and POAG risk. Homozygous subjects for the C allele had a higher POAG risk than carriers of the ancestral G allele (adjusted odds ratio 1.73, 95% confidence interval 1.13-2.65, p=0.011). This association remained statistically significant after adjustment for multiple comparisons. We also confirmed the association between the rs1279683 polymorphism and a higher POAG risk in GG homozygous subjects and detected statistically significant differences in SLC23A2 gene expression between POAG cases and controls, even after adjustment for multiple testing. We observed a nominally significant (p<0.05) gene-gene interaction between the SEC14L2/TAP and SLC23A2 polymorphisms in determining POAG risk, increasing POAG risk in those subjects who had both risk genotypes at the same time (p<0.01). This increase was statistically significant even after adjustment for multiple comparisons. We did not detect any association with POAG risk for the rs6994076 or rs757228 polymorphisms. We also found that POAG patients had statistically significant (after correction for multiple testing) lower plasma vitamin E (p<0.001) and vitamin C (p<0.001) concentrations than control subjects. However, we detected a higher plasma GPx activity in POAG cases than in controls (p<0.001). The rs6994076 and rs1279683 polymorphisms were significantly (p<0.001) associated with plasma vitamin E and vitamin C, respectively. However, the rs757228 polymorphism in the GPX4 gene was not associated with plasma GPx activity. CONCLUSIONS: We have described a novel association between the rs737723 polymorphism (SEC14L2/TAP) and higher POAG risk and confirmed the association between rs1279683 (SLC23A2) and POAG. Our results also suggested a gene-gene interaction between both polymorphisms that increases POAG risk.

Biochemical-molecular-genetic biomarkers in the tear film, aqueous humor, and blood of primary open-angle glaucoma patients.

Introduction: Glaucoma is a chronic neurodegenerative disease, which is the leading cause of irreversible blindness worldwide. As a response to high intraocular pressure, the clinical and molecular glaucoma biomarkers indicate the biological state of the visual system. Classical and uncovering novel biomarkers of glaucoma development and progression, follow-up, and monitoring the response to treatment are key objectives to improve vision outcomes. While the glaucoma imaging field has successfully validated biomarkers of disease progression, there is still a considerable need for developing new biomarkers of early glaucoma, that is, at the preclinical and initial glaucoma stages. Outstanding clinical trials and animal-model study designs, innovative technology, and analytical approaches in bioinformatics are essential tools to successfully uncover novel glaucoma biomarkers with a high potential for translation into clinical practice. Methods: To better understand the clinical and biochemical-molecular-genetic glaucoma pathogenesis, we conducted an analytical, observational, and case-comparative/control study in 358 primary open-angle glaucoma (POAG) patients and 226 comparative-control individuals (CG) to collect tears, aqueous humor, and blood samples to be processed for identifying POAG biomarkers by exploring several biological pathways, such as inflammation, neurotransmitter/neurotrophin alteration, oxidative stress, gene expression, miRNAs fingerprint and its biological targets, and vascular endothelial dysfunction, Statistics were done by using the IBM SPSS 25.0 program. Differences were considered statistically significant when p ≤ 0.05. Results: Mean age of the POAG patients was 70.03 ± 9.23 years, and 70.62 ± 7.89 years in the CG. Malondialdehyde (MDA), nitric oxide (NO), interleuquin (IL)-6, endothelin-1 (ET-1), and 5 hydroxyindolacetic acid (5-HIAA), displayed significantly higher levels in the POAG patients vs. the CG (p < 0.001). Total antioxidant capacity (TAC), brain derived neurotrophic factor (BDNF), 5-hydroxy tryptamine (5-HT), solute carrier family 23-nucleobase transporters-member 2 (SLC23A2) gene, and the glutathione peroxidase 4 (GPX4) gene, showed significantly lower levelsin the POAG patients than in the CG (p < 0.001). The miRNAs that differentially expressed in tear samples of the POAG patients respect to the CG were the hsa miR-26b-5p (involved in cell proliferation and apoptosis), hsa miR-152-3p (regulator of cell proliferation, and extracellular matrix expression), hsa miR-30e-5p (regulator of autophagy and apoptosis), and hsa miR-151a-3p (regulator of myoblast proliferation). Discussion: We are incredibly enthusiastic gathering as much information as possible on POAG biomarkers to learn how the above information can be used to better steer the diagnosis and therapy of glaucoma to prevent blindness in the predictable future. In fact, we may suggest that the design and development of blended biomarkers is a more appropriate solution in ophthalmological practice for early diagnosis and to predict therapeutic response in the POAG patients.

Oxidative Stress Mediates Epigenetic Modifications and the Expression of miRNAs and Genes Related to Apoptosis in Diabetic Retinopathy Patients.

Knowledge on the underlying mechanisms and molecular targets for managing the ocular complications of type 2 diabetes mellitus (T2DM) remains incomplete. Diabetic retinopathy (DR) is a major cause of irreversible visual disability worldwide. By using ophthalmological and molecular-genetic approaches, we gathered specific information to build a data network for deciphering the crosslink of oxidative stress (OS) and apoptosis (AP) processes, as well as to identify potential epigenetic modifications related to noncoding RNAs in the eyes of patients with T2DM. A total of 120 participants were recruited, being classified into two groups: individuals with T2MD (T2MDG, n = 67), divided into a group of individuals with (+DR, n = 49) and without (-DR, n = 18) DR, and a control group (CG, n = 53). Analyses of compiled data reflected significantly higher plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and significantly lower total antioxidant capacity (TAC) in the +DR patients compared with the -DR and the CG groups. Furthermore, the plasma caspase-3 (CAS3), highly involved in apoptosis (AP), showed significantly higher values in the +DR group than in the -DR patients. The microRNAs (miR) hsa-miR 10a-5p and hsa-miR 15b-5p, as well as the genes BCL2L2 and TP53 involved in these pathways, were identified in relation to DR clinical changes. Our data suggest an interaction between OS and the above players in DR pathogenesis. Furthermore, potential miRNA-regulated target genes were identified in relation to DR. In this concern, we may raise new diagnostic and therapeutic challenges that hold the potential to significantly improve managing the diabetic eye.

Understanding Neurodegeneration from a Clinical and Therapeutic Perspective in Early Diabetic Retinopathy.

Recent evidence indicates that neurodegeneration is a critical element of diabetic retinopathy (DR) pathogenesis. The neuronal cells' apoptosis contributes to microvascular impairment and blood-retinal barrier breakdown. Therefore, neurodegeneration represents an early intervention target to slow and prevent the development of microvascular alterations visible on clinical examination. Multimodal imaging features and functional assessment can permit the identification of neuronal damage in a subclinical stage before the recognition of DR signs. Clinical features of neurodegeneration are crucial in identifying patients at high risk of developing a vascular impairment and, thus, serve as outcome measures to understand the efficacy of supplementation. The optimal approach for targeting neurodegeneration contemplates the use of topical compounds that possibly act on different elements of the pathogenic cascade. To date, clinical trials available on humans tested three different topical agents, including brimonidine, somatostatin, and citicoline, with promising results.

Association between a SLC23A2 gene variation, plasma vitamin C levels, and risk of glaucoma in a Mediterranean population.

PURPOSE: Several dietary factors have been associated with glaucoma. Among them, dietary antioxidant intake (i.e., vitamin C and vitamin A) in association with glaucoma has been analyzed, but with mixed results. Genetic factors may play a role in modulating the effect of dietary antioxidant intake on glaucoma; however, nutrigenetic studies in this field are scarce. Our aim was to study the association between selected polymorphisms in key proteins related to vitamin C and vitamin A concentrations and primary open-angle glaucoma (POAG). METHODS: We performed a case-control study matched for age, sex, and bodyweight. We recruited 300 subjects (150 POAG cases and 150 controls) from a Mediterranean population and determined the plasma concentrations of vitamin C and vitamin A for each subject. We selected the following single-nucleotide polymorphisms (SNPs) in genes related to vitamin A and vitamin C concentrations: rs176990 and rs190910 in the retinol-binding protein 1 (RBP1) gene; and rs10063949 and rs1279683 in the Na⁺-dependent L-ascorbic acid transporters 1 and 2, respectively (encoded by the SLC23A1 and SLC23A2 genes). RESULTS: We found a statistically significant association between the rs1279386 (A>G) SNP in SLC23A2 and POAG risk. In the crude analysis, homozygous subjects for the G allele (GG subjects) had higher risk of POAG than other genotypes (OR: 1.67; 95% CI: 1.03-2.71). This association remained statistically significant (p=0.010) after multivariate adjustment for potential confounders. We also found that POAG patients had lower plasma vitamin C concentrations than control subjects (9.9±1.7 µg/ml versus 11.7±1.8 µg/ml, p<0.001). Moreover, we consistently detected a significant association between the rs1279386 SNP in SLC23A2 and plasma vitamin C concentrations: GG subjects had significantly lower plasma vitamin C concentrations than the other genotypes (9.0±1.4 µg/ml versus 10.5±1.6 µg/ml, p<0.001 in POAG cases and 10.9±1.6 µg/ml versus 12.1±1.8 µg/ml, p<0.001 in controls). The rs10063949 SNP in SLC23A1 was not associated with either plasma vitamin C concentrations or POAG risk. Similarly, SNPs in RBP1 were not associated with vitamin A concentrations or POAG risk. CONCLUSIONS: The rs1279683 SNP in SLC23A2 was significantly associated with lower plasma concentrations of vitamin C and with higher risk of POAG in GG subjects.

The Role of Autophagy in Eye Diseases.

Autophagy is a catabolic process that ensures homeostasis in the cells of our organism. It plays a crucial role in protecting eye cells against oxidative damage and external stress factors. Ocular pathologies of high incidence, such as age-related macular degeneration, cataracts, glaucoma, and diabetic retinopathy are of multifactorial origin and are associated with genetic, environmental factors, age, and oxidative stress, among others; the latter factor is one of the most influential in ocular diseases, directly affecting the processes of autophagy activity. Alteration of the normal functioning of autophagy processes can interrupt organelle turnover, leading to the accumulation of cellular debris and causing physiological dysfunction of the eye. The aim of this study is to review research on the role of autophagy processes in the main ocular pathologies, which have a high incidence and result in high costs for the health system. Considering the role of autophagy processes in cell homeostasis and cell viability, the control and modulation of autophagy processes in ocular pathologies could constitute a new therapeutic approach.

miRNAs and Genes Involved in the Interplay between Ocular Hypertension and Primary Open-Angle Glaucoma. Oxidative Stress, Inflammation, and Apoptosis Networks.

Glaucoma has no cure and is a sight-threatening neurodegenerative disease affecting more than 100 million people worldwide, with primary open angle glaucoma (POAG) being the most globally prevalent glaucoma clinical type. Regulation of gene expression and gene networks, and its multifactorial pathways involved in glaucoma disease are landmarks for ophthalmic research. MicroRNAs (miRNAs/miRs) are small endogenous non-coding, single-stranded RNA molecules (18-22 nucleotides) that regulate gene expression. An analytical, observational, case-control study was performed in 42 patients of both sexes, aged 50 to 80 years, which were classified according to: (1) suffering from ocular hypertension (OHT) but no glaucomatous neurodegeneration (ND) such as the OHT group, or (2) have been diagnosed of POAG such as the POAG group. Participants were interviewed for obtaining sociodemographic and personal/familial records, clinically examined, and their tear samples were collected and frozen at 80 °C until processing for molecular-genetic assays. Tear RNA extraction, libraries construction, and next generation sequencing were performed. Here, we demonstrated, for the first time, the differential expression profiling of eight miRNAs when comparing tears from the OHT versus the POAG groups: the miR-26b-5p, miR-152-3p, miR-30e-5p, miR-125b-2-5p, miR-224-5p, miR-151a-3p, miR-1307-3p, and the miR-27a-3p. Gene information was set up from the DIANA-TarBase v7, DIANA-microT-CDS, and TargetScan v7.1 databases. To build a network of metabolic pathways, only genes appearing in at least four of the following databases: DisGeNet, GeneDistiller, MalaCards, OMIM PCAN, UniProt, and GO were considered. We propose miRNAs and their target genes/signaling pathways as candidates for a better understanding of the molecular-genetic bases of glaucoma and, in this way, to gain knowledge to achieve optimal diagnosis strategies for properly identifying HTO at higher risk of glaucoma ND. Further research is needed to validate these miRNAs to discern the potential role as biomarkers involved in oxidative stress, immune response, and apoptosis for the diagnosis and/or prognosis of OHT and the prevention of glaucoma ND.

Is Saffron Able to Prevent the Dysregulation of Retinal Cytokines Induced by Ocular Hypertension in Mice?

Cytokine- and chemokine-mediated signalling is involved in the neuroinflammatory process that leads to retinal ganglion cell (RGC) damage in glaucoma. Substances with anti-inflammatory properties could decrease these cytokines and chemokines and thus prevent RGC death. The authors of this study analysed the anti-inflammatory effect of a hydrophilic saffron extract standardized to 3% crocin content, focusing on the regulation of cytokine and chemokine production, in a mouse model of unilateral laser-induced ocular hypertension (OHT). We demonstrated that following saffron treatment, most of the concentration of proinflammatory cytokines (IL-1ß, IFN-γ, TNF-α, and IL-17), anti-inflammatory cytokines (IL-4 and IL-10), Brain-derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth Factor (VEGF), and fractalkine were unaffected in response to laser-induced OHT in both the OHT eye and its contralateral eye. Only IL-6 levels were significantly increased in the OHT eye one day after laser induction compared with the control group. These results differed from those observed in animals subjected to unilateral OHT and not treated with saffron, where changes in cytokine levels occurred in both eyes. Therefore, saffron extract regulates the production of proinflammatory cytokines, VEGF, and fractalkine induced by increasing intraocular pressure (IOP), protecting the retina from inflammation. These results indicate that saffron could be beneficial in glaucoma by helping to reduce the inflammatory process.

Searching for the Antioxidant, Anti-Inflammatory, and Neuroprotective Potential of Natural Food and Nutritional Supplements for Ocular Health in the Mediterranean Population.

Adherence to a healthy diet offers a valuable intervention to compete against the increasing cases of ocular diseases worldwide, such as dry eye disorders, myopia progression, cataracts, glaucoma, diabetic retinopathy, or age macular degeneration. Certain amounts of micronutrients must be daily provided for proper functioning of the visual system, such as vitamins, carotenoids, trace metals and omega-3 fatty acids. Among natural foods, the following have to be considered for boosting eye/vision health: fish, meat, eggs, nuts, legumes, citrus fruits, nuts, leafy green vegetables, orange-colored fruits/vegetables, olives-olive oil, and dairy products. Nutritional supplements have received much attention as potential tools for managing chronic-degenerative ocular diseases. A systematic search of PubMed, Web of Science, hand-searched publications and historical archives were performed by the professionals involved in this study, to include peer-reviewed articles in which natural food, nutrient content, and its potential relationship with ocular health. Five ophthalmologists and two researchers collected the characteristics, quality and suitability of the above studies. Finally, 177 publications from 1983 to 2021 were enclosed, mainly related to natural food, Mediterranean diet (MedDiet) and nutraceutic supplementation. For the first time, original studies with broccoli and tigernut (chufa de Valencia) regarding the ocular surface dysfunction, macular degeneration, diabetic retinopathy and glaucoma were enclosed. These can add value to the diet, counteract nutritional defects, and help in the early stages, as well as in the course of ophthalmic pathologies. The main purpose of this review, enclosed in the Special Issue "Health Benefits and Nutritional Quality of Fruits, Nuts and Vegetables," is to identify directions for further research on the role of diet and nutrition in the eyes and vision, and the potential antioxidant, anti-inflammatory and neuroprotective effects of natural food (broccoli, saffron, tigernuts and walnuts), the Mediterranean Diet, and nutraceutic supplements that may supply a promising and highly affordable scenario for patients at risk of vision loss. This review work was designed and carried out by a multidisciplinary group involved in ophthalmology and ophthalmic research and especially in nutritional ophthalmology.

Signature of Circulating Biomarkers in Recurrent Non-Infectious Anterior Uveitis. Immunomodulatory Effects of DHA-Triglyceride. A Pilot Study.

The purpose of this study was to identify circulating biomarkers of recurrent non-infectious anterior uveitis (NIAU), and to address the anti-inflammatory effects of triglyceride containing docosahexaenoic acid (DHA-TG). A prospective multicenter study was conducted in 72 participants distributed into: patients diagnosed with recurrent NIAU in the quiescence stage (uveitis group (UG); n = 36) and healthy controls (control group (CG); n = 36). Each group was randomly assigned to the oral supplementation of one pill/day (+) containing DHA-TG (n = 18) or no-pill condition (-) (n = 17) for three consecutive months. Data from demographics, risk factors, comorbidities, eye complications and therapy were recorded. Blood was collected and processed to determine pro-inflammatory biomarkers by bead-base multiplex assay. Statistical processing with multivariate statistical analysis was performed. The mean age was 50, 12 (10, 31) years. The distribution by gender was 45% males and 55% females. The mean number of uveitis episodes was 5 (2). Higher plasma expression of interleukin (IL)-6 was detected in the UG versus the CG (p = 5 × 10-5). Likewise, significantly higher plasma levels were seen for IL-1ß, IL-2, INFγ (p = 10-4), and TNFα (p = 2 × 10-4) in the UG versus the CG. Significantly lower values of the above molecules were found in the +DHA-TG than in the -DHA-TG subgroups, after 3 months of follow-up, TNFα (p = 10-7) and IL-6 (p = 3 × 10-6) being those that most significantly changed. Signatures of circulating inflammatory mediators were obtained in the quiescent stage of recurrent NIAU patients. This 3-month follow-up strongly reinforces that a regular oral administration of DHA-TG reduces the inflammatory load and may potentially supply a prophylaxis-adjunctive mediator for patients at risk of uveitis vision loss.

The role of neuroinflammation in the pathogenesis of glaucoma neurodegeneration.

The chapter is a review enclosed in the volume "Glaucoma: A pancitopatia of the retina and beyond." No cure exists for glaucoma. Knowledge on the molecular and cellular alterations underlying glaucoma neurodegeneration (GL-ND) includes innovative and path-breaking research on neuroinflammation and neuroprotection. A series of events involving immune response (IR), oxidative stress and gene expression are occurring during the glaucoma course. Uveitic glaucoma (UG) is a prevalent acute/chronic complication, in the setting of chronic anterior chamber inflammation. Managing the disease requires a team approach to guarantee better results for eyes and vision. Advances in biomedicine/biotechnology are driving a tremendous revolution in ophthalmology and ophthalmic research. New diagnostic and imaging modalities, constantly refined, enable outstanding criteria for delimiting glaucomatous neurodegeneration. Moreover, biotherapies that may modulate or inhibit the IR must be considered among the first-line for glaucoma neuroprotection. This review offers the readers useful and practical information on the latest updates in this regard.

Computational Analysis of Clinical and Molecular Markers and New Theranostic Possibilities in Primary Open-Angle Glaucoma.

Primary open-angle glaucoma (POAG) is a paramount cause of irreversible visual disability worldwide. We focus on identifying clinical and molecular facts that may help elucidating the pathogenic mechanisms of the disease. By using ophthalmological approaches (biomicroscopy, ocular fundus, optical coherence tomography, and perimetry) and experimental tests (enzyme-linked immunosorbent assay (ELISA), high performance liquid chromatography (HPLC), and Western blot/immunoblotting) directed to evaluate the oxidative stress, inflammation, apoptosis, and neurodegeneration processes, we gather information to build a network of data to perform a computational bioinformatics analysis. Our results showed strong interaction of the above players and its downstream effectors in POAG pathogenesis. In conclusion, specific risk factors were identified, and molecules involved in multiple pathways were found in relation to anterior and posterior eye segment glaucoma changes, pointing to new theranostic challenges for better managing POAG progression.

Clinical and Molecular-Genetic Insights into the Role of Oxidative Stress in Diabetic Retinopathy: Antioxidant Strategies and Future Avenues.

Reactive oxygen species (ROS) overproduction and ROS-signaling pathways activation attack the eyes. We evaluated the oxidative stress (OS) and the effects of a daily, core nutritional supplement regimen containing antioxidants and omega 3 fatty acids (A/ω3) in type 2 diabetics (T2DM). A case-control study was carried out in 480 participants [287 T2DM patients with (+)/without (-) diabetic retinopathy (DR) and 193 healthy controls (CG)], randomly assigned to a daily pill of A/ω3. Periodic evaluation through 38 months allowed to outline patient characteristics, DR features, and classic/OS blood parameters. Statistics were performed by the SPSS 24.0 program. Diabetics displayed significantly higher circulating pro-oxidants (p = 0.001) and lower antioxidants (p = 0.0001) than the controls. Significantly higher plasma malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS; p = 0.006) and lower plasma total antioxidant capacity (TAC; p = 0.042) and vitamin C (0.020) was found in T2DM + DR versus T2DM-DR. The differential expression profile of solute carrier family 23 member 2 (SLC23A2) gene was seen in diabetics versus the CG (p = 0.001), and in T2DM + DR versus T2DM - DR (p < 0.05). The A/ω3 regime significantly reduced the pro-oxidants (p < 0.05) and augmented the antioxidants (p < 0.05). This follow-up study supports that a regular A/ω3 supplementation reduces the oxidative load and may serve as a dietary prophylaxis/adjunctive intervention for patients at risk of diabetic blindness.

Beneficial effects of saffron (Crocus sativus L.) in ocular pathologies, particularly neurodegenerative retinal diseases.

Saffron (Crocus sativus L.) has been traditionally used in food preparation and as a medicinal plant. It currently has numerous therapeutic properties attributed to it, such as protection against ischemia, as well as anticonvulsant, antidepressant, anxiolytic, hypolipidemic, anti-atherogenic, anti-hypertensive, antidiabetic, and anti-cancer properties. In addition, saffron has remarkable beneficial properties, such as anti-apoptotic, anti-inflammatory and antioxidant activities, due to its main metabolites, among which crocin and crocetin stand out. Furthermore, increasing evidence underwrites the possible neuroprotective role of the main bioactive saffron constituents in neurodegenerative diseases, such as Parkinson's and Alzheimer's diseases, both in experimental models and in clinical studies in patients. Currently, saffron supplementation is being tested for ocular neurodegenerative pathologies, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration and glaucoma, among others, and shows beneficial effects. The present article provides a comprehensive and up to date report of the investigations on the beneficial effects of saffron extracts on the main neurodegenerative ocular pathologies and other ocular diseases. This review showed that saffron extracts could be considered promising therapeutic agents to help in the treatment of ocular neurodegenerative diseases.

Smoking, an additional risk factor in elder women with primary open-angle glaucoma.

PURPOSE: Smoking is a serious public health problem worldwide. Some authors refer to it as the "silent epidemic of the 20th century." It constitutes an important risk factor for ocular pathologies such as age-related macular degeneration (ARMD), diabetic retinopathy, and neuropathy because the toxic effects of tobacco play a key role in the deterioration of eye tissue. Damage to trabecular meshwork cells (TMC) and retinal ganglion cells (RGC), involving inflammation and apoptosis mechanisms, has been proved in glaucoma. The aim of this study was to determine whether smoking influences the progression of primary open angle glaucoma (POAG) in women. METHODS: This experimental study involved a sampling of consecutive cases of smokers, ex-smokers and non-smokers women with POAG. One hundred and twenty women with POAG, aged 40-90 years, were enrolled (40 smokers, 40 ex-smokers and 40 non-smokers). Samples of aqueous humor (AH) and plasma from each subject were obtained at the beginning of the surgical procedures. Both inflammation and apoptosis processes in the subjects were studied by means of enzyme immunoassay and western blot procedures respectively. We analyzed the interleukin-6 (IL-6) levels as an inflammation marker and the expression of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) as apoptosis markers. RESULTS: IL-6, caspase-3, and PARP-1 levels were significantly higher in the smoker women who smoked than in the ex-smoker and non-smoker glaucomatous groups of the same gender (p<0,05). CONCLUSIONS: Inflammation and apoptosis marker levels increase with smoking in the aqueous humor and plasma samples of POAG women. Smoking could be an important additional risk factor for glaucoma progression in elderly women.

Antioxidant status modifications by topical administration of dorzolamide in primary open-angle glaucoma.

PURPOSE: This study deals with the role of the topical administration of dorzolamide eyedrops on the oxidative/antioxidant status of aqueous humor in patients with primary open angle glaucoma (POAG). METHODS: A case-control study including 130 patients distributed into three groups was carried out: 1) patients with POAG without dorzolamide instillation administration (GG; n=34); 2) patients with POAG with dorzolamide (DG; n=36); and 3) subjects with cataracts (comparative group, CG; n=60). Oxidative activity was measured in the aqueous humor by malondialdehyde determination by the thiobarbituric acid reactive substances assay. Antioxidant status was assessed in the aqueous humor samples by measuring the superoxide dismutase activity and the total antioxidant status. RESULTS: Oxidative activity was significantly higher in both glaucoma groups than in the cataracts group (GG vs CG, p=3.68 E-34; DG vs CG, p=5.11 E-45) and was significantly higher in GG than in DG (p=0.0034). SOD activity was significantly higher in both glaucoma groups than in the cataracts group (GG vs CG, p=1.08 E-14; DG vs CG, p=3.70 E-22), and was significantly higher in GG than in DG (p=0.018). Finally, total antioxidant status was significantly decreased in both glaucoma groups compared with the cataracts group (GG vs CG, p=2.51 E-12; DG vs CG, p=5.06 E-05), and was more significantly decreased in GG than in DG (p=9.23 E-07). CONCLUSIONS: Topical administration of dorzolamide colirium diminishes oxidative stress in patients with glaucoma.