Write short notes on carbohydrate metabolism in the lens
Nathaniel Knox Cartwright, Petros Carvounis in Short Answer Questions for the MRCOphth Part 1, 2018
Alternatively, glucose may be used by the sorbitol pathway:– under euglycaemic conditions about 5% of glucose is reduced to sorbitol by aldose reductase– sorbitol is then metabolised to fructose by polyol dehydrogenase. This enzyme has a low affinity; therefore in hyperglycaemic conditions, large amounts of sorbitol may accumulate which can cause osmotic pressure. This pathway is thought to be relevant to the formation of diabetic cataracts– similarly, in conditions of elevated galactose levels (i.e. galactosaemia), galactose may be reduced to dulcitol by aldose reductase. Dulcitol is not a substrate for polyol dehydrogenase and will accumulate, leading to cataracts.
Diabetes and the Microcirculation
John H. Barker, Gary L. Anderson, Michael D. Menger in Clinically Applied Microcirculation Research, 2019
Several agents show promise for the future treatment of diabetic microvascular complications. The aldose reductase inhibitors, which inhibit polyol pathway activity, have shown marked benefits in experimental diabetes. In contrast, studies in human subjects have so far been disappointing and there have been problems with toxic side effects; however, most studies to date have looked at aldose reductase inhibitors in established microvascular disease and it may be that they are more effective in prevention. In neuropathy, regeneration and repair of myelinated fibers have been observed in sural nerve biopsy specimens from patients treated with sorbinil,66 and decreased glomerular hyperfiltration has been seen with ponalrestat.67 Another treatment that has shown great promise in experimental diabetes is inhibition of the advanced stages of protein glycation using aminoguanidine; however, no clinical trials have yet been reported using this agent.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Peter Grunwald in 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).
Application of disaccharides alone and in combination, for the improvement of stability and particle properties of spray-freeze dried IgG
Published in Pharmaceutical Development and Technology, 2019
Behnaz Daneshmand, Homa Faghihi, Maryam Amini Pouya, Shabnam Aghababaie, Majid Darabi, Alireza Vatanara
Spray-freeze dried powder of IgG formulation, in the absence of disaccharides, contained high values of soluble aggregates after the process and 3 months storage (Table 1). Short-term stability of all preparations was desirably preserved. No loss of monomer recovery was detected in F3 (Mannitol:IgG at a weight ratio of 2:1) and F9 (Lactose:Sorbitol:IgG at a weight ratio of 1:1:1). F10 consisted of Sorbitol:Mannitol:IgG at a weight ratio of 1:1:1, demonstrating the highest amount of aggregates, immediately after the procedure. The stability of formulations was unpredictably influenced by sugar/polyol type and ratio under storage condition. F1, F2, F5, and F6 were favorably stabilized with the aggregate percent of less than 5%. Extensively reduced monomer was observed in F3, F8, and F9 even more than pure IgG. It can be concluded that Trehalose, Lactose, Trehalose-Lactose, and Trehalose-Mannitol were formulations of choice in terms of monomer recovery of IgG via SFD and within storage. On the contrary, Mannitol alone, Mannitol-Lactose, Mannitol-Sorbitol, and Lactose-Sorbitol deteriorated protein stability at 45°C.
Aldose reductase inhibitors: 2013-present
Published in Expert Opinion on Therapeutic Patents, 2019
Luca Quattrini, Concettina La Motta
In 2013, Milan Stefek and co-worker exploited the natural scaffold of quercetin to develop a novel class of ALR2 inhibitors [86]. They functionalized at least one phenolic residue of the flavonol derivative with electrophilic residues like the 2-chloro-1,4-naphthoquinone, the 4-O-acetylferuloyl chloride, and the 3-chloro-2,2-dimethylpropanoyl chloride, and succeeded in obtaining potent inhibitors endowed with a concomitant antioxidant efficacy. A representative example of the class, 47–49, characterized by the presence of the mentioned residues in position 4ʹ of the nucleus, are depicted in Figure 8. Adding antioxidant properties to compounds able to block the polyol pathway via ALR2 inhibition can ameliorate the pharmacological profile of the resulting derivatives, since in this metabolic pathway an increased quantity of ROS can be produced, worsening diabetes-induced tissue damage at different levels. Furthermore, in principle, treatment with antioxidants can keep the enzyme in the reduced form, thus preventing the development of drug resistance following its oxidative modification at the Cys298 residue.
Effects of xylitol and erythritol consumption on mutans streptococci and the oral microbiota: a systematic review
Published in Acta Odontologica Scandinavica, 2020
Eva Söderling, Kaisu Pienihäkkinen
Xylitol is a five-carbon polyol sweetener that appears to have specific, beneficial effects on oral health [10–12]. It is also a prebiotic, increasing the numbers of bifidobacteria in the large intestine of humans [13]. Habitual consumption of xylitol is suggested to reduce caries occurrence, plaque and MS numbers [10–12]. In addition to xylitol chewing gums, also pastilles and wipes have been shown to decrease MS counts [14,15]. Oral rinses have not shown this effect, most probably due to short exposure times [16]. Interestingly, maternal consumption of xylitol was associated with a significant reduction in mother–child transmission of MS [17]. Also, prenatal and perinatal xylitol chewing by mothers delayed S. mutans carriage in children [18]. Systematic reviews on the caries-preventive effect of xylitol have resulted in varying outcomes [19,20]. In the literature, however, the MS-reducing effect of xylitol is often acknowledged even though not all existing studies confirm this effect [21]. This is reflected for example in the Policy on the Use of Xylitol by the American Academy of Pediatric Dentistry (2015) which concludes that there is a lack of consistent evidence showing significant reductions in MS in children associated with the use of xylitol [22]. The studies on the effects of xylitol on MS counts, published before 2000, have been reviewed by Maguire and Rugg-Gunn [10]. The majority of these studies were published by Finnish researchers. Most of the studies published before the year 2000 probably suffer from a high risk of bias, at least in terms of reporting the methods used, when taking into consideration the present demands for RCTs.
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