Low apparent aldose reductase activity produced by monosaccharide autoxidation

Low apparent aldose reductase activity, as measured by NADPH oxidation, can be produced by the spontaneous autoxidation of monosaccharides. NADPH is oxidized to metabolically active NADP+ in a solution of autoxidizing DL-glyceraldehyde at rates of up to 15 X 10(-4) A340/min. The close parallelism between the effects of buffer salt type and concentration, monosaccharide structure and temperature activation on autoxidation and NADPH oxidation imply that autoxidation is a prerequisite for the NADPH oxidation, probably via the hydroperoxy radical. Nucleotide-binding proteins enhanced NADPH oxidation induced by DL-glyceraldehyde, up to 10.6-fold with glucose-6-phosphate dehydrogenase. Glutathione reductase-catalysed NADPH oxidation in the presence of autoxidizing monosaccharide showed many characteristics of the aldose reductase reaction. Aldose reductase inhibitors acted as antioxidants in inhibiting this NADPH oxidation. These results indicate that low apparent aldose reductase activities may be due to artifacts of monosaccharide autoxidation, and could provide an explanation for the non-linear steady-state kinetics observed with DL-glyceraldehyde and aldose reductase.

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Effects of NaCl, glucose, and aldose reductase inhibitors on cloning efficiency of renal medullary cells

AJP Cell Physiology ◽

10.1152/ajpcell.1990.258.1.c156 ◽

1990 ◽

Vol 258 (1) ◽

pp. C156-C163 ◽

Cited By ~ 55

Author(s):

P. H. Yancey ◽

M. B. Burg ◽

S. M. Bagnasco

Keyword(s):

Aldose Reductase ◽

High Glucose ◽

Reductase Activity ◽

Cloning Efficiency ◽

Glucose Levels ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors ◽

Colony Forming Efficiency ◽

Forming Efficiency ◽

Osmotic Balance

To analyze the effects of sorbitol accumulation on the survival and growth of epithelial cells from rabbit renal inner medulla, cloning efficiency (an index of cell viability) was measured at normal and high glucose and NaCl concentrations and when sorbitol accumulation was prevented by Tolrestat and Sorbinil, which inhibit aldose reductase. With PAP-HT25 cells grown to near confluence, high NaCl increases aldose reductase activity, causing enough rise in cell sorbitol concentration to balance most of the increased osmolality of the high extracellular NaCl. Inhibition of aldose reductase prevents both the increased enzyme activity and sorbitol accumulation in a dose-related manner. Paralleling this, colony-forming efficiency is not affected by the inhibitors at a normal NaCl concentration but is greatly reduced when extracellular NaCl is high. On the other hand, high glucose levels, as occur in diabetes, increase sorbitol content well above the concentration required for osmotic balance and inhibit colony-forming efficiency. Under those conditions, aldose reductase inhibitors lower cell sorbitol and reverse (at 300-350 mosmol/kgH2O) or reduce (at 500-550 mosmol/kgH2O) the decrease in colony-forming efficiency caused by high glucose. Thus sorbitol accumulation is necessary for osmoregulation when induced by high osmolality but is harmful when induced by high glucose.

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Intracellular betaine substitutes for sorbitol in protecting renal medullary cells from hypertonicity

AJP Renal Physiology ◽

10.1152/ajprenal.1991.260.4.f494 ◽

1991 ◽

Vol 260 (4) ◽

pp. F494-F497 ◽

Cited By ~ 4

Author(s):

T. Moriyama ◽

A. Garcia-Perez ◽

A. D. Olson ◽

M. B. Burg

Keyword(s):

Aldose Reductase ◽

Reductase Activity ◽

Organic Osmolytes ◽

Cloning Efficiency ◽

Hypertonic Medium ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors ◽

Nacl Concentration ◽

Medullary Cells

Renal medullary cells are normally exposed to a variably high extracellular NaCl concentration. They compensate by accumulating large amounts of organic osmolytes, including sorbitol and betaine. The sorbitol is synthesized from glucose, catalyzed by aldose reductase. Previously, inhibition of aldose reductase activity was noted to greatly reduce renal medullary cell survival and growth (measured by cloning efficiency) in tissue cultures of renal medullary cells in hypertonic medium. In contrast, inhibition of aldose reductase and renal medullary sorbitol accumulation is not associated with kidney damage in vivo. In the present experiments we find that addition of betaine to the medium, and its resultant uptake by the cells, largely replaces the decrease in sorbitol caused by aldose reductase inhibitors and restores the cloning efficiency. We presume that in vivo uptake of betaine by renal medullary cells similarly protects them from harm when aldose reductase inhibitors lower sorbitol. The results also demonstrate that one organic osmolyte can substitute for another in protecting cells from hypertonicity, consistent with the compatible osmolytes hypothesis.

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Molecular Docking Studies of Novel Arylidene-2, 4-Thiazolidinediones as Potential Aldose Reductase Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180811310070007 ◽

2013 ◽

Vol 10 (7) ◽

pp. 604-612 ◽

Cited By ~ 1

Author(s):

Manoj Gautam ◽

Suresh Thareja

Keyword(s):

Molecular Docking ◽

Aldose Reductase ◽

Docking Studies ◽

Molecular Docking Studies ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors

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The role of aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy

The Medical Journal of Australia ◽

10.5694/j.1326-5377.1994.tb138210.x ◽

1994 ◽

Vol 160 (1) ◽

pp. 45-45 ◽

Cited By ~ 1

Author(s):

M Wright ◽

Shill ◽

Marie Anne Slaney

Keyword(s):

Peripheral Neuropathy ◽

Aldose Reductase ◽

Diabetic Peripheral Neuropathy ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors

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Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

Molecules ◽

10.3390/molecules26102867 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2867

Author(s):

Lucia Kovacikova ◽

Marta Soltesova Prnova ◽

Magdalena Majekova ◽

Andrej Bohac ◽

Cimen Karasu ◽

...

Keyword(s):

Aldose Reductase ◽

Diabetic Complications ◽

Therapeutic Potential ◽

Ex Vivo ◽

Biological Activities ◽

In Vivo Models ◽

Aldose Reductase Inhibitors ◽

Reductase Inhibitors ◽

Promising Therapeutic Approach

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed.

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NADPH-dependent reduction of 2,6-dichlorophenol-indophenol by the phagocytic vesicles of pig polymorphonuclear leucocytes

Biochemical Journal ◽

10.1042/bj2100577 ◽

1983 ◽

Vol 210 (2) ◽

pp. 577-581 ◽

Cited By ~ 24

Author(s):

H Wakeyama ◽

K Takeshige ◽

S Minakami

Keyword(s):

Oxidation Rate ◽

Cetyltrimethylammonium Bromide ◽

Reductase Activity ◽

Tween 20 ◽

Polymorphonuclear Leucocytes ◽

Resting Cells ◽

Low Concentrations ◽

Km Value ◽

Nadph Oxidation

NADPH-dependent 2,6-dichlorophenol-indophenol (DCIP) reductase activity in the homogenate of phagocytosing pig polymorphonuclear leucocytes was twice that of the resting cells and the activity in the phagocytic vesicles corresponded to the activity increment due to phagocytosis. The apparent Km value of the reductase activity in the vesicles for NADPH was 30 microM, which is similar to that of the NADPH-dependent superoxide (O2-) formation. Increasing the DCIP reductase activity by increasing the DCIP concentration caused a decrease in the O2- –forming activity, the NADPH oxidation rate being constant and independent of the dye concentration. p-Chloromercuribenzoate and cetyltrimethylammonium bromide at low concentrations inhibited the O2- –forming activity of the vesicles without inhibiting the DCIP reductase. Quinacrine inhibited both O2- formation and DCIP reduction. The DCIP reductase activity could be extracted with a mixture of deoxycholate and Tween-20, which extracts the O2- –forming activity. The reductase activity in the extract was enhanced 2-fold by the addition of FAD, and its apparent Km was 0.085 microM. These results indicate that the NADPH-dependent DCIP reductase activity of the phagocytic vesicles is catalysed by a flavin-containing component of the O2- –forming system.

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