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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The polyol pathway enzyme aldose reductase (for an overview on docking studies with aldose reductase inhibitors see Zeyad et al., 2016) is implicated in diabetic complications. In the case of hyperglycemia glucose becomes reduced by aldose reductase at the expense of NADPH to sorbitol that subsequently is converted to fructose in presence of NAD+. The resulting shortage of NADPH and NAD+ leads among others to diminished glutathione levels associated with enhanced occurrence of oxidative stress and inflammatory processes, e.g., in eyes (retinopathy), heart (cardiovascular disease), kidney (nephropathy), and nerves and feet (neuropathy). The tripeptide glutathione (cysteine, glutamic acid, and glycine) is present in most mammalian tissue and acts as an antioxidant, a free radical scavenger and a detoxifying agent. The relation between cancer as well as other chronic diseases and oxidative stress relies on the fact that oxidative stress activates transcription factors (NF-κB, AP-1, p53, HIF-1α, PPAR-γ, β-catenin/Wnt, Nrf2, MAFK, etc.) leading to the expression of several hundred genes encoding growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti-inflammatory molecules (Reuter et al., 2010; Sosa et al., 2013; Okita et al., 2017).
Marine Algae in Diabetes and Its Complications
Published in Se-Kwon Kim, Marine Biochemistry, 2023
Complications involving the small and large blood vessels are likely to occur in uncontrolled diabetes. The danger of developing diabetic complications depends upon the period and harshness of diabetes. Complications of the microvasculature in diabetes include retinopathy, nephropathy, and neuropathy. Retinopathy is possibly the most common complication of chronic diabetes, known to affect around 10,000 people and producing fresh incidences of blindness every year. Aldose reductase participates in the development of microvascular and macrovascular impediments. Hyperactivity of aldose reductase in hyperglycemic episode results in the accumulation of sorbitol in cells. Sorbitol, being impermeable, exerts hyperosmotic stress and causes pain. Non-enzymatic glycosylation of important plasma proteins attributes to the formation of advanced glycated end (AGE) products. Oxidative stress also contributes to cell injury in hyperglycemia. Antioxidant treatment may ease some vascular complications connected to diabetes. Diabetic retinopathy can be background or proliferative. Background retinopathy typifies tiny hemorrhages in the retinal layer at the center appearing as “dots”, hence, called “dot hemorrhages”. Proliferative retinopathy is symbolized by neoangiogenesis on the retinal surface causing vitreous hemorrhage, sometimes identified by “cotton wool spots”. Diabetic nephropathy is one of the main etiologies of renal failure, described by proteinuria above 500 mg within 24 hours of diabetes onset, but this is followed by hypoproteinuria, or “microalbuminuria”. This phenomenon is frequent to both types of diabetes. The renal pathological changes include increased thickness of the basement membrane of glomeruli, formation of mesangial nodules (Kimmelsteil-Wilson bodies), and microaneurysm, besides others. The core mechanism of damage probably involves a few or all of the etiologies as diabetic retinopathy (Fowler, 2008).
Bio-medical potential of chalcone derivatives and their metal complexes as antidiabetic agents: a review
Published in Journal of Coordination Chemistry, 2021
Hyperglycaemic conditions in bloodstreams are an important aspect of diabetes mellitus and certain secondary complications related to heart, nerves, retina and kidney that come along as a domino effect [56, 57]. These complications occur because of the accretion of ROS viz. reactive oxygen species inside the cells of tissues of diabetes mellitus. Glucose in bloodstreams undergoes its major metabolic fate that is glycolysis, glycogen synthesis and fatty acid synthesis. In hyperglycemia conditions, insulin dependent adipose tissues are stimulated by insulin to consume glucose. But, when adipose tissues become resistant to insulin or in the case of limited insulin secretion, micro vascular tissues of retina, kidney, liver, red blood cells, neurons, and peripheral nerves play a part to normalize the glucose concentration in bloodstreams since they are independent of insulin stimulus. Since their glucose transporters do not need insulin to be present over the membrane, they get more and more glucose into the cells. So, they follow a polyol pathway as an alternative way for glucose fluidity, which is believed to be increased by 33% of total consumption of glucose by tissues in their studies of Flemingia species extracts [58, 59]. In the polyol pathway, aldose reductase is the first key enzyme which transforms glucose into sorbitol by metabolizing aldehydes and carbonyls into alcohols using NADPH [60]. The mechanism of the polyol pathway is shown in Scheme 2.