Unveiling the Nanotechnology-Based Drug Delivery Systems and Patent Literature for Diabetic Retinopathy

Diabetes mellitus is a principal reason for globally developing chronic microvascular disorders defined as diabetic retinopathy (DR). Proliferative retinopathy and non-proliferative retinopathy are the two types of DR. Long-term diabetes, and poor blood sugar and arterial blood pressure regulation are the key risk factors for the onset and advancement of DR. A variety of biochemical pathways are involved in the pathogenesis of DR, which includes increased polyol pathway fluxes, advanced glycation end product growth, protein kinase C isoform activation, and increased hexosamine pathway flux. The varieties of cells are involved in diabetic retinopathy, including glial cells, retinal ganglion cells, endothelial cells, and pericytes. Surgical treatment of DR includes laser treatment, panretinal photocoagulation, focal laser photocoagulation, and vitrectomy surgery. The systemic treatment of DR includes glycemic management and control of blood pressure and hyperlipidemia. Nanotechnology-based formulations like nanoparticles, polymeric nanomicelles, and nanocarrier composite, and various patented formulations have been investigated for the treatment of DR.

Abstract 12508: Nicotinamide Restores Tissue NAD + and Improves Mouse Survival After Cardiac Arrest

Introduction: Metabolic suppression in the ischemic heart is characterized by NAD + depletion. How nicotinamide (NAM) supplementation affects NAD + repletion and cardiac arrest outcomes is unknown. Hypothesis: We hypothesized that NAM supplementation restores tissue NAD + and promotes glucose oxidation and sorbitol clearance, resulting in improved cardiac function and survival in a mouse model of cardiac arrest. Methods: Adult C57BL6 mice were subjected to an established KCL-induced 8 min cardiac arrest, randomly assigned to receive saline (NS) or 100 mg/kg NAM during cardiopulmonary resuscitation (CPR). Survival, MAP, ETCO 2, and ECG were monitored for 4 h after the return of spontaneous circulation (ROSC). Direct cardiac effects were assessed using a cardiomyocyte stunning model and an isolated rat heart Langendroff model to measure the contraction recovery and cardiac function, respectively. NAD + , lactate and ATP were measured by assay kits and AMPK phosphorylation was measured by Western blot. Results: Cardiomyocyte NAD + content decreased from 4.51 ± 0.03 nMol/g pre-ischemia to 2.69 ± 0.42 nMol/g at the end of ischemia. Treatment with 0.01 mM NAM completely restored the cellular level of NAD + and improved contractile recovery by 10 min reperfusion (58.1 ± 7.3% of baseline contractile velocity vs.18.5 ± 3.7% in control cells). NAM administered immediately after ROSC significantly improved mouse survival, with 10/10 survival at 4 h as compared to 5/10 in the NS group. NAM-treated mice displayed improved NAD + content in hearts obtained at 4 h post-ROSC compared to saline treated hearts (4.5 ± 0.1 nMol/g vs. 2.4 ± 0.1 nMol/g). NAM significantly reduced sorbitol accumulation in heart from saline control of 20.4 ± 2.7 μMol/g to 7.2 ± 1.5 μMol/g at 30 min post-ROSC, indicating less glucose shunting to polyol pathway. Cardiac contractile function was completely recovered with 1 mM NAM treatment in the isolated perfused rat heart. Compared with buffer control, NAM treatment increased heart content of NAD + , lactate, ATP and phosphorylated AMPK. Conclusion: NAM is efficacious for restoring cardiac NAD + and promotes metabolic and contractile recovery, with improved survival of cardiac arrest.

EFFECT OF SUPERCRITICAL FLUID EXTRACT OF ZINGIBER OFFICINALIS IN THE MANAGEMENT OF DIABETES AND ITS RELATED COMPLICATIONS

Diabetes mellitus is referred as diabetes which is the metabolic disorder. Major symptoms of diabetes include increased urination & thrust, head ache, high degree of sudden weight loss. Due to increase in blood glucose levels it causes trigger of various pathways which ultimately leads to various diabetic complications. Pathways like which includes Polyol Pathway, Hexosamine Pathway, Activation of PK-C (Protein Kinase-C), & formation of Advance Glycation End Products. For the diagnosis of diabetes two major tests are done blood glucose level and Glycated hemoglobin content (HbA1c). Ayurveda is the super bank for various molecules to treat any disease. Here we have chosen the super critical fluid extract of Ginger that is Zingiber Officinale. In our study we have used Streptozotocin induced diabetes mellitus model by using rats. Our result showed promising effects in the streptozotocine induced diabetes and immunomodulatory activity was also shown by the extract. Overall in conclusion it Zingiber Officinale supercritical fluid extract can be considered as source of multitalented molecules which can be proven better for the management of diabetes and its related

Physiological and Pathological Roles of Aldose Reductase

Aldose reductase (AR) is an aldo-keto reductase that catalyzes the first step in the polyol pathway which converts glucose to sorbitol. Under normal glucose homeostasis the pathway represents a minor route of glucose metabolism that operates in parallel with glycolysis. However, during hyperglycemia the flux of glucose via the polyol pathway increases significantly, leading to excessive formation of sorbitol. The polyol pathway-driven accumulation of osmotically active sorbitol has been implicated in the development of secondary diabetic complications such as retinopathy, nephropathy, and neuropathy. Based on the notion that inhibition of AR could prevent these complications a range of AR inhibitors have been developed and tested; however, their clinical efficacy has been found to be marginal at best. Moreover, recent work has shown that AR participates in the detoxification of aldehydes that are derived from lipid peroxidation and their glutathione conjugates. Although in some contexts this antioxidant function of AR helps protect against tissue injury and dysfunction, the metabolic transformation of the glutathione conjugates of lipid peroxidation-derived aldehydes could also lead to the generation of reactive metabolites that can stimulate mitogenic or inflammatory signaling events. Thus, inhibition of AR could have both salutary and injurious outcomes. Nevertheless, accumulating evidence suggests that inhibition of AR could modify the effects of cardiovascular disease, asthma, neuropathy, sepsis, and cancer; therefore, additional work is required to selectively target AR inhibitors to specific disease states. Despite past challenges, we opine that a more gainful consideration of therapeutic modulation of AR activity awaits clearer identification of the specific role(s) of the AR enzyme in health and disease.

Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions

Pyruvate functions as a key molecule in energy production and as an antioxidant. The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; however, its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. We observed rapid and extensive cell death under high-glucose (> 10 mM) and pyruvate-starved conditions. Exposure of Schwann cells to these conditions led to a significant decrease in glycolytic flux, mitochondrial respiration and ATP production, accompanied by enhanced collateral glycolysis pathways (e.g., polyol pathway). Cell death could be prevented by supplementation with 2-oxoglutarate (a TCA cycle intermediate), benfotiamine (the vitamin B1 derivative that suppresses the collateral pathways), or the poly (ADP-ribose) polymerase (PARP) inhibitor, rucaparib. Our findings suggest that exogenous pyruvate plays a pivotal role in maintaining glycolysis–TCA cycle flux and ATP production under high-glucose conditions by suppressing PARP activity.

The polyol pathway is an evolutionarily conserved system for sensing glucose uptake

SummaryCells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion depends on an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway is required for the glucose-induced nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP’s nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for the glucose uptake that allows metabolic remodeling.