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Postimplantation diabetic embryopathy
Published in Moshe Hod, Lois G. Jovanovic, Gian Carlo Di Renzo, Alberto de Leiva, Oded Langer, Textbook of Diabetes and Pregnancy, 2018
Ulf J. Eriksson, Parri Wentzel
Using an inbred Sprague Dawley strain (L) with about 20% skeletal malformations when the mother is diabetic and inbred Wistar Furth rats (no diabetes-inducible skeletal malformations), a global gene linkage analysis of the skeletal malformations was performed with microsatellites, a study that yielded strong coupling of the malformations to 7 regions on chromosomes 4, 10, 14, 18, and 19 and a weaker coupling to 14 other loci in the genome; altogether we found loci on 16 chromosomes. Searching for candidate genes within a distance of 10 cM from each microsatellite yielded 18 genes that had been implicated in previous studies of diabetic embryopathy. These genes were involved in embryonic development/morphogenesis (Map1b, Shh, Tgfb3, Vegfa, Dvl2, Nf1, Gsk3b, Gap43, Tgfbr3, Gdf1, Csf1r),308–314 regulation of DNA/RNA metabolism (En2, Brcc3, Tp53),192,308,315–317 regulation of apoptosis (Nol3, Bak1),308 and cellular metabolism (Folr1, Akr1b1).149,168,315
AGE-RAGE Axis in the Aging and Diabetic Heart
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Karen M. O’Shea, Ann Marie Schmidt, Ravichandran Ramasamy
Glucose metabolism via the polyol pathway plays an important role in the generation of reactive carbonyl intermediates and AGEs. Aldose reductase, encoded by the human gene AKR1B1, is a cytoplasmic enzyme that reduces aldehydes. As the rate-limiting enzyme that catalyzes the first step of the polyol pathway, aldose reductase converts glucose to sorbitol in a NADPH-dependent manner. Sorbitol is then converted to fructose by sorbitol dehydrogenase at the cost of depletion of NAD+. Sorbitol and fructose accumulate in diabetic hearts when flux through the polyol pathway is increased due to high levels of glucose, leading to the generation of AGEs (Chung and Chung 2003). Fructose can be phosphorylated by fructose-3-phosphokinase into fructose-3-phosphate, which itself can modify and directly interact with proteins, lipids, and nucleic acids or be converted into AGE precursor3-deoxyglucosone. Additionally, the depletion of NAD+ and increased NADH/NAD+ that occurs as a result of increased flux through the polyol pathway inhibits NAD+-dependent enzymes, including GAPDH. This results in accumulation of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate, both of which are precursors for methylglyoxal (Rabbani and Thornalley 2015).
Intra-site differential inhibition of multi-specific enzymes
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Mario Cappiello, Francesco Balestri, Roberta Moschini, Umberto Mura, Antonella Del-Corso
The multifaceted activities of AKR1B1 have antagonistic effects that depend on the substrate undergoing reduction, and drug development from ARIs has been relatively poor when compared to the in vitro discovery of selective and potent inhibitors of the enzyme. Thus, we propose a new strategy to approaching AKR1B1 inhibition15 and use terms such as “aldose reductase differential inhibitors” (ARDIs) and “intra site differential inhibition” to refer to molecules and conditions, respectively, which are able to determine an inhibition of the enzyme depending on the nature of the substrate the enzyme is working on. Within this frame, useful ARDIs include molecules able to intervene on glucose reduction, leaving unaltered, or less affected, the detoxifying activity of the enzymes towards hydrophobic aldehydes. Molecules able to differentially inhibit the reduction of GSHNE with respect to toxic hydrophobic aldehydes may be valuable, because of the inflammatory potential associated with GSHNE reduction.
Soyasaponins from Zolfino bean as aldose reductase differential inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Francesco Balestri, Marinella De Leo, Carlo Sorce, Mario Cappiello, Luca Quattrini, Roberta Moschini, Carlotta Pineschi, Alessandra Braca, Concettina La Motta, Federico Da Settimo, Antonella Del-Corso, Umberto Mura
The rationale behind these investigations is based on the apparent link, in hyperglycaemic conditions, between sorbitol over-production and reducing power failure due to the AKR1B1 action and the development in diabetic subjects of pathological states such as retinopathy, nephropathy, peripheral neuropathy, cardiac dysfunctions, and cataracts9. Evidence of the effectiveness of yuchasaponins from the flower buds of Camellia oleifera as aldose reductase inhibitors (ARIs) on the rat lens enzyme has been reported10. More recently, in vitro inhibition of aldose reductase in a crude liver homogenate and in vivo inhibition of the enzyme in streptozotocin-induced diabetic rats, were reported for a furostanol saponin and its derivatives, extracted from Balanites aegyptiaca11,12. A triterpenoid oleanane saponin has also been reported to interfere with the polyol pathway through aldose reductase inhibition both in vivo in diabetic rats, and in an in vitro model of diabetic peripheral neuropathy13.
Novel 2-phenoxypyrido[3,2-b]pyrazin-3(4H)-one derivatives as potent and selective aldose reductase inhibitors with antioxidant activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Xin Hao, Gang Qi, Hongxing Ma, Changjin Zhu, Zhongfei Han
Diabetes mellitus (DM) is a metabolic disorder resulting from defects in insulin secretion, insulin action, or both1. People suffering from DM are vulnerable to chronic diabetic complications, including neuropathy, retinopathy, nephropathy, and cataracts, which are the major menace to diabetic patients2,3. Increasing clinical research indicated that the abnormal polyol pathway flux of blood glucose is obviously related to pathogenesis of diabetes complications4. Normally, the blood glucose is predominantly converted to glucose-6-phosphate by hexokinase and then enters the glycolytic pathway. However, at high glucose concentration, specifically in diabetics, the combining capacity of aldose reductase (AKR1B1) to glucose is motivated and about one-third of the total glucose is metabolised through the polyol pathway in tissues such as lens, kidney, retina, and peripheral nerves5–7. In polyol pathway (Figure 1), AKR1B1 is the first enzyme and catalyses the reduction of glucose by NADPH to sorbitol, which can, in turn, be oxidised by the enzyme sorbitol dehydrogenase with concomitant reduction of NAD+. In the tissues implicated in these pathologies, the increased polyol pathway flux would directly cause the accumulation of sorbitol, which is hard to penetrate through cellular membranes, resulting in osmotic imbalance, cell swelling, and membrane permeability changes. All these AKR1B1-mediated biochemical alterations contribute to the pathogenesis of diabetic complications8–10. Therefore, design and synthesis aldose reductase inhibitors (ARIs) to inhibit the activity of AKR1B1 and further regulate the polyol pathway of glucose are likely to be a promising therapy to prevent the development of diabetic complications.