Integrative study of gene expression datasets in retinal samples of Diabetic Retinopathy.

Diabetic Retinopathy is prevalent among patients with uncontrolled hyperglycemia resulting in vision loss. Despite numerous challenges to create a link among these conditions, the characterization of pathological neovascularization causing retinal damage due to the prognosis of early non-proliferative diabetic retinopathy to late proliferative diabetic retinopathy needs deep understanding. In this study, meta-analysis-based integration of gene expression datasets for the fibrovascular membrane of PDR and neural retina of NPDR were compared, to investigate the differentially expressed genes involved in retinal angiogenesis. Human samples with gene expression profiling of the same experiment type and platform with sufficient information for analysis were included in the study. The studies from cell lines and non-human studies, human samples that include serum, cornea, lens, and/or other ocular tissues or fluids, and studies that lack basic information for analysis were excluded. The microarray datasets available in the Gene Expression Omnibus database of the early and late stages in DR were screened to find common gene expression profiles. Using the INMEX bioinformatics tool, significantly upregulated and downregulated genes in the neural retina of Non-Proliferative Diabetic Retinopathy and fibrovascular membrane of Proliferative Diabetic Retinopathy were compared and studied by the combine effect size method. Using the STRING database PPI network, 50 upregulated and 50 downregulated genes were used to find the key candidate genes involved in retinal disease/degeneration in eye/retinal tissues. In the extensive gene expression meta-analysis performed using INMEX bioinformatics tool, overall, 7935 differentially expressed genes were identified and the respective heatmap was created by using the visualization tools of INVEX. STRING database PPI network identified Retinol Binding Protein 3, Neural Retina Leucine Zipper, S-Antigen Visual Arrestin, Peripherin 2, and Aryl Hydrocarbon Receptor Interacting Protein Like-1 to be the most highly ranked hub genes. The newly discovered potential genes related to retinal angiogenesis causing FVM formation in DR may provide insight into the cellular pathogenesis of NPDR to PDR.

Microvascular cells: A special focus on heterogeneity of pericytes in diabetes associated complications.

Pericytes (PC) are microvascular mural cells that make specific cell-to-cell contacts with the endothelial cells (EC). These cells are obligatory constituents of the microvessels including the retinal vasculature and they serve as regulators of vascular development, stabilization, maturation and remodeling. During early stages of diabetic retinopathy (DR), apoptotic loss of PC surrounding the retinal vasculature occurs. This may lead to reduced vessel stability, the onset of EC apoptosis, and subsequent retinal ischemia leading to angiogenesis and eventually, severe vision loss due to late proliferative diabetic retinopathy (PDR). Similarly, diabetic nephropathy (DN) is a chronic kidney disease due to hyperglycemia that particularly affects renal PC. Chronic high blood glucose level causes migration of peritubular PC away from the capillary into the interstitial space, which destabilizes the micro vessels, resulting in microvascular rarefaction. In both diabetes associated complications, the identification of specific biomarkers is necessary to stabilize the PC at an early stage. This review largely covers the importance of PC towards the pathogenesis of diabetes associated complications, and their heterogeneity in healthy and angiogenic vasculature.

Early structural and functional neurovascular changes in the retina in the prediabetic stage.

PURPOSE: This study was undertaken to investigate the neurovascular changes in the retina of prediabetic subjects. METHODS: Subjects enroled in a prospective study were separated into prediabetic and normal control groups based on their glycosylated haemoglobin (HbA1C) levels, fasting and postprandial blood sugar levels and glucose tolerance test. All the subjects underwent detailed ophthalmic evaluation, which included fundus examination, fundus photography, optical coherence tomography angiography (OCTA), and multifocal electroretinogram (mfERG). Comparisons were done between the groups using the Wilcoxon signed rank test. RESULTS: The median age was 48 years for the normal controls (n = 40), and 49.5 years for prediabetic subjects (n = 45) (p = 0.306). There was no difference in the vision, contrast sensitivity, thickness of the ganglion cell complex or the foveal avascular zone parameters between the groups. But the central foveal thickness and subfoveal choroidal thickness were significantly reduced in prediabetics (p < 0.01). The mfERG showed significant differences in the amplitude. The average amplitude was 35 ± 12 nv/deg2 in the normals and 29 ± 11 nv/deg2 in the prediabetics (p = 0.003). A weak positive correlation was noted between the mfERG and vascular parameters in the prediabetic group. CONCLUSIONS: The prediabetic stage reveals earliest functional neuronal changes in the retina. The neuronal function seems to be affected much earlier than clinically appreciable structural changes in the ganglion cell complex and precedes vascular changes in the retina.

Elevated serum OxLDL is associated with progression of type 2 Diabetes Mellitus to diabetic retinopathy.

Hyperlipidemia is associated with the progression of diabetic retinopathy (DR). Paraoxonase 1 (PON1), an esterase is known to prevent systemic LDL oxidation. This study assessed if serum oxLDL is associated with the progression of Type 2 DM to DR. This study is part of a three-year hospital based prospective study where 87 subjects were recruited. This included T2DM without DR (n = 22); Non-Proliferative (NPDR) (n = 21) and Proliferative DR (PDR) (n = 22) along with age/sex matched controls (n = 22). Serum oxLDL-Ab was estimated by ELISA. Serum PON esterase activity and plasma Malondialdehyde (MDA) level were estimated by spectrophotometry and the serum Advanced Glycation End products (AGE) level by spectroflourimetry. The systemic levels of oxLDL, AGE and MDA were increased with the progression of T2DM without DR to DR as seen by ANOVA (P < 0.05). Serum oxLDL-Ab levels showed a positive correlation to total cholesterol (P = 0.04) as evaluated in the DR group. Statin intake was found to lower PON esterase activity (P < 0.05). Based on this pilot study, it is proposed that elevated serum oxLDL should be validated in larger cohort studies to ensure it could be potential risk factor for the progression of T2DM to DR.

Agonistic effect of polyunsaturated fatty acids (PUFAs) and its metabolites on brain-derived neurotrophic factor (BDNF) through molecular docking simulation.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a potent neurotrophic factor that is implicated in the regulation of food intake and body weight. Polyunsaturated fatty acids (PUFAs) localised in cell membranes have been shown to alter the levels of BDNF in the brain, suggesting that PUFAs and BDNF could have physical interaction with each other. To decipher the molecular mechanism through which PUFAs modulates BDNF's activity, molecular docking was performed for BDNF with PUFAs and its metabolites, with 4-Methyl Catechol as a control. RESULTS: Inferring from molecular docking studies, lipoxin A4 (LXA4), and a known anti-inflammatory bioactive metabolite derived from PUFAs, with a binding energy of -3.98 Kcal/mol and dissociation constant of 1.2 mM showed highest binding affinity for BDNF in comparison to other PUFAs and metabolites considered in the study. Further, the residues Lys 18, Thr 20, Ala 21, Val 22, Phe 46, Glu 48, Lys 50, Lys 58, Thr 75, Gln 77, Arg 97 and Ile 98 form hot point motif, which on interaction enhances BDNF's function. CONCLUSION: These results suggest that PUFAs and their metabolites especially, LXA4, modulate insulin resistance by establishing a physical interaction with BDNF. Similar interaction(s) was noted between BDNF and resolvins and protectins but were of lesser intensity compared to LXA4.