Polyol accumulation

Lee AYW, Chung SK, Chung SSM. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. 

The most potent inhibitor among a group of flavonoids studied by Varma and Kinoshita [28], was quercitrin 2"-acetate (Table 8.4, No. 4) (50% at 4 x 10- 8 M), which decreased polyol accumulation by 58% at 1 x 10 5 M in the intact rat lens. In contrast to most flavonoids, it is water-soluble and was... 

Polyol accumulation is directly dependent on blood glucose concentrations. Sorbitol and fructose are polyols derived from glucose by an enzymatic process facilitated by the enzyme Aldose... 

Chronic Complications - A great deal of interest has been generated in recent years, regarding the possibility that polyol accumulation may be fundamental to the development of diabetic complications in certain tissues. While sorbitol accumulation in the lens has long been implicated as being causally related to diabetic cataract formation , more recent work has provided compelling evidence that a similar situation may exist for the development of diabetic neuropathy " and macroangio-pathy. ... 

Hyperglycemia, protein glycation, and the Maillard reaction, in themselves, do not appear to explain adequately the pathogenesis of diabetic complications or the variability in their expression. Other theories, such as the aldose reductase hypothesis of polyol accumulation are also subject to similar inadequacies (Hunt and Wolff, 1991a Wolff et al., 1991). 

A. (2004) Polyol accumulation by Aspergillus oryzae at low water activity in solid-state fermentation. Microbiology, 150, 1095-1101. 

Polyols are present in desiccation tolerant lichens and liverworts, although not in mosses (Lewis, 1984). More generally starch hydrolysis and sugar accumulation occur in many plants experiencing severe water deficits (Hsiao, 1973). It is tempting to speculate that the accumulation of low molecular weight solutes in reponse to water stress represents a mechanism for the protection of membranes and proteins in the dry state. 

Accumulation of compatible solutes (glycine betaine, proline and polyols such as mannitol, sorbitol and pinitol) occurs in many droughted plants and they act as cytoplasmic osmotica for osmotic adjustment. However, they may have other functions which include enhancing the stability of macromolecules and membranes (Paleg, Stewart Starr, 1985 Smirnoff Stewart, 1985 Chapter 7). 

The presence of particles in the brains of experimental rats and humans exposed to asbestos has been reported (Pontefiart and Cunningham, 1973 Auerbach et al., 1980). In experimental studies, particles of Teflon, a reflux paste, enter the brain via intravascular transport when injected into the bladder (Aaronson et al., 1993). Encephalitic reactions to accumulated calcium oxalate crystals in the brain as a result of infusions of glucose surrogate polyol solutions have been described (PciflPcr etal., 1984). Such studies indicate the capacity of particulates to enter the brain and thus pose a potential pathological threat to the functioning of the central nervous system (CNS). 

Pyrrolo[2,3-c]carbazole alkaloids (see Schemes 2.70-2.72) isolated from the dark green marine sponge, Dictyodendrilla sp., showed inhibitory activity against bovine lens aldose reductase catalyzing the reduction of aldoses to polyols which, on accumulation in cells, may result in diabetes. These alkaloids could provide prevention from such ailments (250). 

It has long been recognized that boron is required by higher plants [61, 62], and recent research indicates the involvement of boron in three main aspects of plant physiology cell wall structure, membrane function, and reproduction. In vascular plants, boron in solution moves in the transpiration stream from the roots and accumulates in the stems and leaves. Once in the leaves, the translocation of boron is limited and requires a phloem transport mechanism. The nature of this mechanism was only recently elucidated with the isolation of a number of borate polyol compounds from various plants [63-65]. These include sorbitol-borate ester complexes isolated from the floral nectar of peaches and mannitol-borate ester complexes from the phloem sap of celery. The implication is that the movement of boron in plants depends on borate-polyol ester formation with the particular sugar polyol compounds used as transport molecules in specific plants. 

Lens aldose reductase has been implicated in the pathogenesis of cataracts in diabetic and galac-tosemic animals. The enzyme catalyzes the reduction of glucose and galactose to their polyols, which accumulate in large quantities in the lens and ultimately lead to mature lens opacities. Several key bioflavones have activity against this enzyme. Oral administration of quercitrin decreased the accumulation of sobital in the lens. Therefore, the accumulation of lens opacities could be partially abrogated by certain flavonoids. In a study of 30 flavones, 4 isoflavones, and 13 coumarins, many potent inhibitors were found, but 5,7,3, 4 -tetrahydroxy-3,6-dimethoxyflavone and 6,3, 4 -trihy-droxy-5,7,8-trimethoxyflavone were especially active. 

Figure 6.2. (Upper panel) The four major classes of organic osmolytes (I) sugars and polyhydric alcohols (polyols) (II) amino acids and amino acid derivatives (III) methylated ammonium and sulfonium compounds and (IV) urea. (Figure modified after Somero and Yancey, 1997.) (Lower panel) Structures of charged osmolytes accumulated in extremely halophilic archaea (after Martin et al., 1999). Note that these osmolytes commonly represent a type of organic osmolyte that is found in many bacteria or eukaryotes to which a charged group has been attached. Typically, the charged group is anionic, for example, a phosphate or a carboxylate group.

In Ayurveda and folklore medicines, cinnamon is used in the treatment of diabetes. Cinnamon is reported to reduce the blood glucose level in non-insulin-dependent diabetics. Therapeutic studies have proved the potential of cinnamaldehyde as an antidiabetic agent. Cinnamaldehyde inhibits aldose reductase, a key enzyme involved in the polyol pathway. This enzyme catalyses the conversion of glucose to sorbitol in insulin-insensitive tissues in diabetic patients. This leads to accumulation of sorbitol in chronic complications of diabetes, such as cataract, neuropathy and retinopathy. Aldose-reductase inhibitors prevent conversion of glucose to sorbitol, thereby preventing several diabetic complications (Lee, 2002). 

Some typical structural templates embedded with the thiazoHdine frame have been reported as potent inhibitors of aldose reductase (AR), an enzyme in the polyol pathway responsible for the conversion of glucose to sorbitol. In this, the accumulation of sorbitol has been attributed to causing cataracts, neuropathy, and retinopathy in diabetic cases [ 157,158]. The planar hydrophobic (aromatic) regions and propensity to charge transfer interactions have been... 

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