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Pyruvate functions as a key molecule in energy production and as an antioxidant. The efficacy of pyruvate supplementation in diabetic retinopathy and nephropathy has been shown in animal models; however, its significance in the functional maintenance of neurons and Schwann cells under diabetic conditions remains unknown. We observed rapid and extensive cell death under high-glucose (> 10 mM) and pyruvate-starved conditions. Exposure of Schwann cells to these conditions led to a significant decrease in glycolytic flux, mitochondrial respiration and ATP production, accompanied by enhanced collateral glycolysis pathways (e.g., polyol pathway). Cell death could be prevented by supplementation with 2-oxoglutarate (a TCA cycle intermediate), benfotiamine (the vitamin B1 derivative that suppresses the collateral pathways), or the poly (ADP-ribose) polymerase (PARP) inhibitor, rucaparib. Our findings suggest that exogenous pyruvate plays a pivotal role in maintaining glycolysis–TCA cycle flux and ATP production under high-glucose conditions by suppressing PARP activity.

The prevalence and incidence of diabetes mellitus (DM) are increasing worldwide bringing with it a significantly higher rate of complications. Various mechanisms such as carbonyl stress, polyol pathway, oxidative stress, hexosamine pathways, diacylglycerol/protein kinase-C activation, etc., are responsible for the pathogenesis of DM and its complications. Persistent hyperglycaemia and inhibition of metabolising and detoxifying enzymes lead to the excessive synthesis of carbonyl compounds such as methylglyoxal, glyoxal, and 3-deoxyglucosone, resulting in carbonyl stress. The substrates, metabolizing and detoxifying enzymes of carbonyl compounds are discussed. The mechanistic roles of carbonyl compounds and advanced glycation end products (AGEs) in atherosclerosis, insulin resistance, thrombogenicity, and endothelial dysfunction in animal and cell culture model of DM and patients with DM are summarised. Because of the essential role of carbonyl stress, therapeutics are aimed at scavenging, metabolizing, detoxifying, and inhibiting carbonyl compounds or AGEs so that their harmful effects are minimized. Clinically used drugs, plants extracts and miscellaneous chemical with antiglycation properties are used in an animal model of DM to alleviates the impact of carbonyl compounds. Extensive clinical trials with derivatisation of available antiglycation agents to increase the bioavailability and decrease side effects are warranted further.

Cardiovascular disease is one of the leading causes of mortality in diabetes. High fructose consumption has been linked with the development of diabetes and cardiovascular disease. Serum and cardiac tissue fructose levels are elevated in diabetic patients, and cardiac production of fructose via the intracellular polyol pathway is upregulated. The question of whether direct myocardial fructose exposure and upregulated fructose metabolism have potential to induce cardiac fructose toxicity in metabolic stress settings arises. Unlike tightly-regulated glucose metabolism, fructose bypasses the rate-limiting glycolytic enzyme, phosphofructokinase, and proceeds through glycolysis in an unregulated manner. In vivo rodent studies have shown that high dietary fructose induces cardiac metabolic stress and functional disturbance. In vitro, studies have demonstrated that cardiomyocytes cultured in high fructose exhibit lipid accumulation, inflammation, hypertrophy and low viability. Intracellular fructose mediates post-translational modification of proteins, and this activity provides an important mechanistic pathway for fructose-related cardiomyocyte signaling and functional effect. Additionally, fructose has been shown to provide a fuel source for the stressed myocardium. Elucidating the mechanisms of fructose toxicity in the heart may have important implications for understanding cardiac pathology in metabolic stress settings.

The elderly population in the United States is projected to almost double by the year 2050. In addition, the numbers of diabetics are rising, along with its most common complication, diabetic retinopathy (DR). To effectively treat DR within the elderly population, it is essential first to consider the retinal changes that occur due to aging, such as decreased blood flow, retinal thinning, and microglial changes, and understand that these changes can render the retina more vulnerable to oxidative and ischemic damage. Given these considerations, as well as the pathogenesis of DR, specific pathways could play a heightened role in DR progression in elderly patients, such as the polyol pathway and the vascular endothelial growth factor (VEGF) axis. Current ocular treatments include intravitreal corticosteroids, intravitreal anti-VEGF agents, laser photocoagulation and surgical interventions, in addition to better control of underlying diabetes with an expanding range of systemic treatments. While using therapeutics, it is also essential to consider how pharmacokinetics and pharmacodynamics change with aging; oral drug absorption can decrease, and ocular drug metabolism might affect the dosing and delivery methods. Also, elderly patients may more likely be nonadherent to their medication regimen or appointments than younger patients, and undertreatment with anti-VEGF drugs often leads to suboptimal outcomes. With a rising number of elderly DR patients, understanding how aging affects disease progression, pharmacological metabolism, and adherence are crucial to ensuring that this population receives adequate care.

Diabetes mellitus, a disorder of metabolism, results in the elevation of glucose level in the blood. In this hyperglycaemic condition, aldose reductase overexpresses and leads to further complications of diabetes through the polyol pathway. Glucose metabolism-related disorders are the accumulation of sorbitol, overproduction of NADH and fructose, reduction in NAD+, and excessive NADPH usage, leading to diabetic pathogenesis and its complications such as retinopathy, neuropathy, and nephropathy. Accumulation of sorbitol results in the alteration of osmotic pressure and leads to osmotic stress. The overproduction of NADH causes an increase in reactive oxygen species production which leads to oxidative stress. The overproduction of fructose causes cell death and non-alcoholic fatty liver disease. Apart from these disorders, many other complications have also been discussed in the literature. Therefore, the article overviews the aldose reductase as the causative agent and a potential target for the treatment of diabetic complications. So, aldose reductase inhibitors have gained much importance worldwide right now. Several inhibitors, like derivatives of carboxylic acid, spirohydantoin, phenolic derivatives, etc. could prevent diabetic complications are discussed in this article.

International audience; Diabetic neuropathy (DN) is a common and serious diabetes-associated complication that primarily takes place because of neuronal dysfunction in patients with diabetes. Use of current therapeutic agents in DN treatment is quite challenging because of their severe adverse effects. Therefore, there is an increased need of identifying new safe and effective therapeutic agents. DN complications are associated with poor glycemic control and metabolic imbalances, primarily oxidative stress (OS) and inflammation. Various mediators and signaling pathways such as glutamate pathway, activation of channels, trophic factors, inflammation, OS, advanced glycation end products, and polyol pathway have a significant contribution to the progression and pathogenesis of DN. It has been indicated that polyphenols have the potential to affect DN pathogenesis and could be used as potential alternative therapy. Several polyphenols including kolaviron, resveratrol, naringenin, quercetin, kaempferol, and curcumin have been administered in patients with DN. Furthermore, chlorogenic acid can provide protection against glutamate neurotoxicity via its hydrolysate, caffeoyl acid group, and caffeic acid through regulating the entry of calcium into neurons. Epigallocatechin-3-gallate treatment can protect motor neurons by regulating the glutamate level. It has been demonstrated that these polyphenols can be promising in combating DN-associated damaging pathways. In this article, we have summarized DN-associated metabolic pathways and clinical manifestations. Finally, we have also focused on the roles of polyphenols in the treatment of DN.

Aldose reductase, a key enzyme of the polyol pathway catalyses NADPH-dependent reduction of glucose to sorbitol. Increased activity of this enzyme is considered a major factor contributing to the development of diabetic complications hence could be an important target in the treatment of these complications. In this work, a database of sesquiterpenes was prepared and screened for their drug-like properties based on the Lipinski’s rule of 5. The co-crystallised structure of aldose reductase was obtained from the Protein Databank and prepared for docking. In silico docking experiments was performed on Autodock tools using 198 sesquiterpene lactones that passed screening, and compounds with the lowest binding energy and favourable binding interactions were selected for molecular docking simulation. Six of the best ranking compounds selected had binding energies ranging from–11.96 Kcal/mol to -9.45 Kcal/mol and were comparable to the energy of the standard inhibitor Idd594 used in the study. They also show good complementarity in their binding to the residues of the binding pocket. The results suggest that dehydrooopodin (1), 11(S),13-dihydrolactucopicrin (2), and Chrysanin (3) offered potential inhibitory activities toward aldose reductase and may serve as lead compounds for in vivo validation as aldose reductase inhibitors. Keywords: Sesquiterpene lactones, Aldose reductase, Binding energy, Molecular docking, Autodock

In diabetes, increased accumulation of sorbitol has been associated with diabetic complications through polyol pathway. Aldose reductase (AR) is one of the key factors involved in reduction of glucose to sorbitol, thereby its inhibition is important for the management of diabetic complications. In the present study, a series of seven 4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetamide derivatives 3(a–g) were synthesized by the reaction of 5-(4-hydroxy-3-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2a) and 5-(4-methoxybenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl acetic acid (2b) with different amines. The synthesized compounds 3(a–g) were investigated for their in vitro aldehyde reductase (ALR1) and aldose reductase (ALR2) enzyme inhibitory potential. Compound 3c, 3d, 3e, and 3f showed ALR1 inhibition at lower micromolar concentration whereas all the compounds were more active than the standard inhibitor valproic acid. Most of the compounds were active against ALR2 but compound 3a and 3f showed higher inhibition than the standard drug sulindac. Overall, the most potent compound against aldose reductase was 3f with an inhibitory concentration of 0.12 ± 0.01 µM. In vitro results showed that vanillin derivatives exhibited better activity against both aldehyde reductase and aldose reductase. The molecular docking studies were carried out to investigate the binding affinities of synthesized derivatives with both ALR1 and ALR2. The binding site analysis of potent compounds revealed similar interactions as were found by cognate ligands within the active sites of enzymes.

Toona sinensis is a medicinal and edible plant that belongs to the genus Toona of family Meliaceae. Phytochemical investigations carried out on this plant, seven apotirucallane-type triterpenoids (1–7), two cycloartane-type triterpenoids (8–9), four sterols (10–13), two sesquiterpenes (14–15), four phenols (16–19), and one lignin (20) were isolated from the pericarp of T. sinensis by silica gel column and preparative middle pressure liquid chromatography. Their structures were identified by interpretation of NMR and comparison with those reported in the literature. Compounds 11–12, 15–16, and 18 were isolated from the family Meliaceae, compounds 13–14 were obtained from the genus Toona, and compound 19 was obtained from T. sinensis for the first time. Additionally, the cytotoxicity and polyol pathway (PP) inhibitory activities of active constituents were evaluated in rat glomerular mesangial cells cultured under high glucose conditions, suggesting their potential application for a PP inhibitor.

Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive because of low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike WT diabetics, diabeticGlut1+/−mice did not display elevated Glut1 levels in the retina. Furthermore, diabeticGlut1+/−mice exhibited ameliorated ERG defects, inflammation, and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. Retinal pigment epithelium-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabeticGlut1+/−mice, reduction of Glut1 specifically in the retina mitigated polyol accumulation and diminished retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.SIGNIFICANCE STATEMENTDiabetic retinopathy affects one-third of diabetic patients and is the primary cause of vision loss in adults 20-74 years of age. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies, and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in the retina, but not the retinal pigment epithelium, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of diabetic retinopathy.

Abstract Development of diabetic cataract is mainly associated with the accumulation of sorbitol via the polyol pathway through the action of Aldose reductase (AR). Hence, AR inhibitors are considered as potential agents in the management of diabetic cataract. This study explored the AR inhibition potential of Hemidesmus indicus var. pubescens root extract by in silico and ex vivo methods. Molecular docking studies (Auto Dock tool) between β-sitosterol, hemidesminine, hemidesmin-1, hemidesmin-2, and AR showed that β-sitosterol (− 10.2 kcal/mol) and hemidesmin-2 (− 8.07 kcal/mol) had the strongest affinity to AR enzyme. Ex vivo studies were performed by incubating isolated goat lenses in artificial aqueous humor using galactose (55 mM) as cataract inducing agent at room temperature (pH 7.8) for 72 h. After treatment with Vitamin E acetate − 100 µg/mL (standard) and test extract (500 and 1000 µg/mL) separately, the estimation of biochemical markers showed inhibition of lens AR activity and decreased sorbitol levels. Additionally, extract also normalized the levels of antioxidant markers like SOD, CAT, GSH. Our results showed evidence that H. indicus var. pubescens root was able to prevent cataract by prevention of opacification and formation of polyols that underlines its potential as a possible therapeutic agent against diabetic complications. Graphic Abstract

Aldose reductase (AR) is an enzyme of the polyol pathway implicated in long-term effect of diabetes mellitus. The development of new molecules as drugs for the inhibition of this enzyme is a growing area of research. Several in vivo and in vitro studies have been carried out to test the inhibitory effect of many organic compounds against AR, but the results have been limited due to their weak pharmacokinetic parameters and safety profile. In this study, molecular docking and molecular dynamics (MD) simulation were performed to establish the inhibitory effect of two critical bioactive compounds (astaxanthin and zeaxanthin) that were affirmed to be safe and powerful antioxidants. Docking studies revealed that both astaxanthin and zeaxanthin displays good binding affinity and inhibition to AR with binding energies of −5.88 kcal/mol and −5.63 kcal/mol, respectively. In contrast to epalrestat; the standard inhibitor having a binding energy of −5.62 kcal/mol. Amino acid residue analysis has shown that both compounds, including the standard inhibitor, bind to the same site due to their common interaction with Trp20 and Tyr48 at AR catalytic site. To complement molecular docking results, we performed MD simulations. The results show that the binding energies of the standard inhibitor, astaxanthin, and zeaxanthin are −134.3486 kJ/mol, −186.271 kJ/mol, and −123.557 kJ/mol, respectively. In both cases, astaxanthin displays better inhibition to AR followed by the standard inhibitor and zeaxanthin.

Background Aldose reductase (AR) and Advanced glycation end product (AGE) are known to play important roles in the development of diabetic complications. The inhibitors of AR and AGE would be potential agents for the prevention of diabetic complications. Objective The present study was aimed to evaluate the aldose reductase (AR) and advanced glycation end product (AGE) inhibitory potential of pterostilbene for its possible role in the treatment of diabetic complications such as cataract. Materials and methods The compound was studied for its inhibitory activity against rat lens AR (RLAR) and rat kidney AR (RKAR) in vitro along with its ability to inhibit the formation of AGEs. Anticataract activity of pterostilbene was demonstrated using sugar induced lens opacity model in isolated cattle lens. Further, the involvement of pterostilbene in galactosemia in rats was investigated by assessing the key markers in the polyol pathway and the results were compared with that of a potent AR inhibitor, fidarestat. Results Pterostilbene exhibited inhibitory activity against RLAR and RKAR with IC50 values of 5.49 mg/ml (21.4 mM) and 6.40 mg/ml (25.02 mM), respectively. In sugar-induced lens opacity model, pterostilbene displayed a significant protective effect by preventing opacification and formation of polyols in cattle lens. Besides, the compound exhibited in vivo inhibition of galactitol accumulation in lens and sciatic nerves of galactose fed rats. Conclusion The results obtained in the study underline the potential of pterostilbene as possible therapeutic agent against long-term diabetic complications., Graphical abstract

BACKGROUND: One of the main causes of blindness for diabetic patients is cataract. The molecular mechanisms that may be involved in diabetic cataract include polyol pathway flux, increased formation of advanced glycation end products, osmotic stress, and elevated oxidative stress. AIM: The aim of the study was to explore the anticataract activity of the ethanol extract from pericarp of Garcinia mangostana Linn (GML) in Goat eye lens. METHODS: Goat eye lenses separated to five groups were incubated in M199 medium, added by penicillin of 100 U/ml and streptomycin of 0.1 mg/ml in a 37°C incubator with 95% O2 and 5% CO2 for 120 h. Group I served as the normal control. Group II (toxic control) the lenses were added by 30 mM glucose. The lenses in Groups III, IV, and V nurtured in M199 medium with 30 mM of glucose added by 100, 500, and 1000 μg/ml of GML pericarp extract. Carboxymethyllysine (CML), GRP78, DDIT3, active caspase 3, and MDA levels were measured by enzyme-linked immunosorbent assay assays. Comparisons of biochemical parameters were conducted using one-way ANOVA with post hoc Tukey test. RESULTS: The administration of glucose 30 mM increased MDA, CML, DDIT3, and GRP78, and active caspase 3 levels in Group II. Groups III, IV, and V which treated with GML pericarp extract decreased MDA, CML, GRP78, and DDIT3, and active caspase 3 levels inside the lens. On lens capsule, the CML and GRP78 levels increased. CONCLUSION: Ethanol extract of GML pericarp potentially showed antioxidant, anti-glycation, DDIT3 inhibitor, and anti-apoptotic activity in Goat cultured lenses.

One of the biochemical abnormalities found in diabetic tissues is a decrease in the cytosolic oxidized to reduced forms of the nicotinamide adenine dinucleotide ratio (NAD+/NADH also known as pseudohypoxia) caused by oxidation of excessive substrates (glucose through the polyol pathway, free fatty acids and lactate). Subsequently, a decline in NAD+ levels as a result of the activation of poly adenine nucleotide diphosphate‐ribose polymerase (mainly in type 1 diabetes) or the inhibition of adenine nucleotide monophosphate‐activated protein kinase (in type 2 diabetes). Thus, replenishment of NAD+ levels by nicotinamide‐related compounds could be beneficial. However, these compounds also increase nicotinamide catabolites that cause oxidative stress. This is particularly troublesome for patients with diabetes, because they have impaired nicotinamide salvage pathway reactions at the level of nicotinamide phosphoribosyl transferase and phosphoribosyl pyrophosphate, which occurs by the following mechanisms. First, phosphoribosyl pyrophosphate synthesis from pentose phosphate pathway is compromised by a decrease in plasma thiamine and transketolase activity. Second, nicotinamide phosphoribosyl transferase expression is decreased because of reduced adenosine monophosphate‐activated protein kinase activity, which occurs in type 2 diabetes. The adenosine monophosphate‐activated protein kinase inhibition is caused by an activation of protein kinase C and D1 as a result of enhanced diacylglycerol synthesis caused by pseudohypoxia and increased fatty acids levels. In this regard, nicotinamide‐related compounds should be given with caution to treat diabetes. To minimize the risk and maximize the benefit, nicotinamide‐related compounds should be taken with insulin sensitizers (for type 2 diabetes), polyphenols, benfotiamine, acetyl‐L‐carnitine and aldose reductase inhibitors. The efficacy of these regimens can be monitored by measuring serum NAD+ and urinary nicotinamide catabolites.

Aldose Reductase 2 (ALR2), the rate-limiting enzyme of the polyol pathway, plays an important role in detoxification of some toxic aldehydes. Under hyperglycemia, this enzyme overactivates and causes diabetic complications (DC). Therefore, ALR2 inhibition has been established as a potential approach to manage these complications. Several ALR2 inhibitors have been reported, but none of them could reach US FDA approval. One of the main reasons is their poor selectivity over ALR1, which leads to the toxicity. The current review underlines the molecular connectivity of ALR2 with DC and comparative analysis of the catalytic domains of ALR2 and ALR1, to better understand the selectivity issues. This report also discusses the key features required for ALR2 inhibition and to limit toxicity due to off-target activity.

A novel antioxidant glutathione liposomes (GSH-LIP) were prepared and applied for diabetic nephropathy therapy. GSH-LIP not only improve the bioavailability and antioxidant capacity of glutathione to scavenge redundant ROS inducing by oxidative stress, but also effectively inhibit the activity of AR and sorbitol accumulation in polyol pathway. The imaging in vivo showed that GSH-LIP could target kidney and significantly improve renal pathology. GSH-LIP may become a new AR inhibitor and antioxidant, which provides a new theoretical basis for the study of drugs for therapy diabetic nephropathy.

The aldose reductase inhibitory activity of extracts from Rosa hybrida petals was evaluated, and a bioactive flavonoid, kaempferol, was isolated from petals via bioassay-guided isolation. Kaempferol was isolated from the ethyl acetate fraction of R. hybrida and was shown to exhibit strong inhibition against aldose reductase (IC50 = 0.02 µM). Quantitative analyses of kaempferol in R. hybrida petals, different flower parts, and different Rosa species were also performed using high-performance liquid chromatography. This study is the first to establish that R. hybrida contains kaempferol and that the light-pink petals of this edible rose species exhibit the highest content of the naturally occurring aldose reductase inhibitor. The results of this study suggested the potential role of R. hybrida petals in the treatment and management of diabetic complications via aldose reductase inhibition.

Numerous studies have implicated oxidative stress in the development of complications of diabetes. During hyperglycemia, production of oxidant agents such as reactive oxygen species and reactive nitrogen species increases. This process, along with a decrease in the activity of antioxidant enzymes, induces oxidative stress in the body. This redox imbalance causes damage to vital biomolecules such as proteins, lipids and DNA and results in the generation of harmful products for the body. Mechanisms associated with the creation of oxidative stress conditions and subsequently complications of diabetes are explained through several pathways such as flux through the polyol pathway, intracellular production of advanced glycation end products precursors, protein kinase-C activation, and increased activities of the hexosamine pathway. On the other hand, the study of polymorphism in the antioxidant enzymes genes indicates that some of the gene polymorphisms reduce the antioxidant power of the enzymes. This article aims to review various studies to demonstrate the effect of oxidative stress on the pathogenesis of diabetes and the positive role of antioxidants on diabetic complications.

Aldose reductase (AR) is the first enzyme of the polyol pathway that has physiological importance under hyperglycaemic conditions. The article has been focussed on AR enzyme inhibition by selected compounds. For this purpose, thein vitroinhibitory effects of various compounds on commercially available recombinant human AR (rAR) enzyme activity were investigated. The IC(50)values of compounds on rAR inhibition effect were found for 6-hydroxy flavone, syringic acid, diosmetin, 6-fluoroflavone, 7-hydroxy-4 '-nitroisoflavone, myricetin as 2.05, 2.97, 15.75, 16.1, 49.5, and 63 mu M, respectively. 6-Hydroxy flavone and syringic acid competitively inhibited rAR with respect to the NADPH with K(i)values 0.509 +/- 0.036 and 0.842 +/- 0.012 mu M. In addition, docking studies were performed to evaluate the potential enzyme binding positions of the compounds. Ourin vitroandin silicoresults indicated that the 6-hydroxy flavone may be a good lead compound in the development of AR inhibitors to prevent diabetic complications., Agri Ibrahim Cecen University Scientific Research [SYO.18.003], This study was financially supported by Agri Ibrahim Cecen University Scientific Research [Project number: SYO.18.003].

Alpha-lipoic acid (ALA) is a substantial antioxidant in the prevention of diabetes and diabetes complications. It can regenerate other antioxidants like vitamin E, vitamin C, Coenzyme Q10 and glutathione and is often known as a universal antioxidant. Antioxidants play a role in diabetes treatment due to hyperglycemia-induced stimulation of the polyol pathway and formation of advanced glycation end products (AGE) and reactive oxygen species (ROS). Clinical trials examining alpha-lipoic acid supplementation on diabetic neuropathy, nephropathy, cardiomyopathy and erectile dysfunction display positive results, particularly in pain amelioration in neuropathy, asymmetric dimethylarginine reductions in nephropathy and improved oscillatory potential and contrast sensitivity in retinopathy. In diabetic cardiomyopathy (DCM), ALA offers protection through inhibition of NF-kB activation, reduction of fas-ligand and decrease in matrix metalloproteinase-2. This comprehensive review summarises and provides an understanding of the importance of alpha- lipoic acid supplementation to prevent diabetes complications.

SummaryCells must adjust the expression levels of metabolic enzymes in response to fluctuating nutrient supply. For glucose, such metabolic remodeling is highly dependent on a master transcription factor ChREBP/MondoA. However, it remains elusive how glucose fluctuations are sensed by ChREBP/MondoA despite the stability of major glycolytic pathways. Here we show that in both flies and mice, ChREBP/MondoA activation in response to glucose ingestion depends on an evolutionarily conserved glucose-metabolizing pathway: the polyol pathway. The polyol pathway converts glucose to fructose via sorbitol. It has been believed that this pathway is almost silent, and its activation in hyperglycemic conditions has deleterious effects on human health. We show that the polyol pathway is required for the glucose-induced nuclear translocation of Mondo, a Drosophila homologue of ChREBP/MondoA, which directs gene expression for organismal growth and metabolism. Likewise, inhibition of the polyol pathway in mice impairs ChREBP’s nuclear localization and reduces glucose tolerance. We propose that the polyol pathway is an evolutionarily conserved sensing system for the glucose uptake that allows metabolic remodeling.

Aldose reductase (AR) and sorbitol dehydrogenase (SDH) are important enzymes of the polyol pathway. In the current study, inhibitory effects of vulpinic acid (VA) carnosic acid (CA) and usnic acid (UA) on purified AR and SDH enzymes were determined. These enzymes inhibition could be essential to prevent diabetic complications. AR and SDH enzymes were purified from sheep kidney. Then, VA, CA and UA were tested in various concentrations against these enzymes activity in vitro. KI values were found to be as 1.46 ± 0.04, 5.13 ± 0.25 and 11.71 ± 0.27 μΜ for VA, CA and UA, respectively, for AR. KI constants were found to be as 15.32 ± 0.34, 145.60 ± 2.17 and 213.40 ± 2.64 μΜ VA, CA and UA, respectively, for SDH. These findings indicate that VA, CA and UA could be useful in the treatment of diabetic complications.Communicated by Ramaswamy H. Sarma.

Aldose reductase (ALR2), one of the metabolically important enzymes, catalyzes the formation of sorbitol from glucose in the polyol pathway. ALR2 inhibition is required to prevent diabetic complications. In the present study, the novel bis-hydrazone compounds bearing isovanillin moiety (GY1-12) were synthesized, and various chromatographic methods were applied to purify the ALR2 enzyme. Afterward, the inhibitory effect of the synthesized compounds on the ALR2 was screened in vitro. All the novel bis-hydrazones demonstrated activity in nanomolar levels as AR inhibitors with IC50 and KI values in the range of 12.55–35.04 nM, and 13.38–88.21 nM, respectively. Compounds GY-11, GY-7, and GY-5 against ALR2 were identified as the highly potent inhibitors, respectively, and were superior to the standard drug, epalrestat. Moreover, a comprehensive ligand-receptor interactions prediction was performed using ADME-Tox, Glide XP, and MM-GBSA modules of Schrodinger Small-Molecule Drug Discovery Suite to elucidate the novel bis-hydrazone derivatives, potential binding modes versus the ALR2. As a result, these compounds with ALR2 inhibitory effects may be potential alternative agents that can be used to treat or prevent diabetic complications.

Prolonged hyperglycemia generates advanced glycation end-products (AGEs), which are believed to be involved in the pathogenesis of diabetic complications. In the present study, we developed a polyclonal antibody against fructose-modified proteins (Fru-P antibody) and identified its epitope as glucoselysine (GL) by NMR and LC-electrospray ionization (ESI)- quadrupole TOF (QTOF) analyses and evaluated its potential role in diabetes sequelae. Although the molecular weight of GL was identical to that of fructoselysine (FL), GL was distinguishable from FL because GL was resistant to acid hydrolysis, which converted all of the FLs to furosine. We also detected GL in vitro when reduced BSA was incubated with fructose for 1 day. However, when we incubated reduced BSA with glucose, galactose, or mannose for 14 days, we did not detect GL, suggesting that GL is dominantly generated from fructose. LC-ESI-MS/MS experiments with synthesized [(13)C(6)]GL indicated that the GL levels in the rat eye lens time-dependently increase after streptozotocin-induced diabetes. We observed a 31.3-fold increase in GL 8 weeks after the induction compared with nondiabetic rats, and Nϵ-(carboxymethyl)lysine and furosine increased by 1.7- and 21.5-fold, respectively, under the same condition. In contrast, sorbitol in the lens levelled off at 2 weeks after diabetes induction. We conclude that GL may be a useful biological marker to monitor and elucidate the mechanism of protein degeneration during progression of diabetes.

Mass extinctions occur frequently in natural history. While studies of animals that became extinct can be informative, it is the survivors that provide clues for mechanisms of adaptation when conditions are adverse. Here, we describe a survival pathway used by many species as a means for providing adequate fuel and water, while also providing protection from a decrease in oxygen availability. Fructose, whether supplied in the diet (primarily fruits and honey), or endogenously (via activation of the polyol pathway), preferentially shifts the organism towards the storing of fuel (fat, glycogen) that can be used to provide energy and water at a later date. Fructose causes sodium retention and raises blood pressure and likely helped survival in the setting of dehydration or salt deprivation. By shifting energy production from the mitochondria to glycolysis, fructose reduced oxygen demands to aid survival in situations where oxygen availability is low. The actions of fructose are driven in part by vasopressin and the generation of uric acid. Twice in history, mutations occurred during periods of mass extinction that enhanced the activity of fructose to generate fat, with the first being a mutation in vitamin C metabolism during the Cretaceous-Paleogene extinction (65 million years ago) and the second being a mutation in uricase that occurred during the Middle Miocene disruption (12-14 million years ago). Today, the excessive intake of fructose due to the availability of refined sugar and high-fructose corn syrup is driving 'burden of life style' diseases, including obesity, diabetes and high blood pressure.

Purpose of review Excessive sugar and particularly fructose consumption has been proposed to be a key player in the pathogenesis of metabolic syndrome and kidney disease in humans and animal models. However, besides its dietary source, fructose can be endogenously produced in the body from glucose via the activation of the polyol pathway. In this review, we aim to describe the most recent findings and current knowledge on the potential role of endogenous fructose production and metabolism in disease. Recent findings Over the recent years, the activation of the polyol pathway and endogenous fructose production has been observed in multiple tissues including the liver, renal cortex, and hypothalamic areas of the brain. The activation occurs during the development and progression of metabolic syndrome and kidney disease and results from different stimuli including osmotic effects, diabetes, and ischemia. Even though the potential toxicity of the activation of the polyol pathway can be attributed to several intermediate products, the blockade of endogenous fructose metabolism either by using fructokinase deficient mice or specific inhibitors resulted in marked amelioration of multiple metabolic diseases. Summary New findings suggest that fructose can be produced in the body and that the blockade of tis metabolism could be clinically relevant for the prevention and treatment of metabolic syndrome and kidney disease.

Hyperglycemia of diabetes mellitus leads to the activation of the polyol way of oxidation of glucose with the activation of the enzymes of aldose reductase and sorbitol dehydrogenase and of their coenzymes NADPH and NAD, which triggers the mechanism of formation of sorbitol. The consequences of these changes lead to microangiopathy of the tissues of the kidneys, which may be one of the pathogenetic mechanisms of diabetic nephropathy. In an accessible literature, the role of coenzymes of sorbitol pathway in the development of diabetic nephropathy is not sufficiently defined. The purpose of the study was to study the content of NAD and NADPH coenzymes, their correlation, and their role in the mechanism of kidney damage in diabetes mellitus and to predict the possible correction of these changes with the NAD-nicotinamide derivative. The study was conducted on a model of streptotrozectinic diabetes mellitus (single administration of streptozotocin in a dose of 60 mg per 1 kg of body weight). Four weeks after induction of diabetes, nicotinamide (100 mg per 1 kg body weight) was injected. The level of glucose was determined by the Accu-chek (Roshe Diagnostics, Switzerland) glucose meter. The content of NAD and NADH was determined in the non-protein extracts. The statistical analysis was carried out using the Microsoft Excel statistical analysis program. The difference between the indicators was considered statistically significant (p

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ± 0.04 and 0.19 ± 0.03 μM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ± 0.02 μM).

Type 2 diabetes is caused by persistent high blood glucose, which is known as diabetic hyperglycemia. This hyperglycemic situation, when not controlled, can overproduce NADH and lower nicotinamide adenine dinucleotide (NAD), thereby creating NADH/NAD redox imbalance and leading to cellular pseudohypoxia. In this review, we discussed two major enzymatic systems that are activated by diabetic hyperglycemia and are involved in creation of this pseudohypoxic condition. One system is aldose reductase in the polyol pathway, and the other is poly (ADP ribose) polymerase. While aldose reductase drives overproduction of NADH, PARP could in contrast deplete NAD. Therefore, activation of the two pathways underlies the major mechanisms of NADH/NAD redox imbalance and diabetic pseudohypoxia. Consequently, reductive stress occurs, followed by oxidative stress and eventual cell death and tissue dysfunction. Additionally, fructose formed in the polyol pathway can also cause metabolic syndrome such as hypertension and nonalcoholic fatty liver disease. Moreover, pseudohypoxia can also lower sirtuin protein contents and induce protein acetylation which can impair protein function. Finally, we discussed the possibility of using nicotinamide riboside, an NAD precursor, as a promising therapeutic agent for restoring NADH/NAD redox balance and for preventing the occurrence of diabetic pseudohypoxia.

Rapidly growing evidence suggests a strong dependence of a polyol pathway enzyme Aldose Reductase (AR) in cancer progression and invasion. Thus, inhibiting the AR through therapeutic inhibitors has a potential application in cancer treatment. Epalrestat (EPR) is the only marketed AR inhibitor with proven safety and efficacy in the management of complications like diabetic neuropathy. However, its short half-life and highly hydrophobic nature restrict its use as an anticancer agent. In the present study, we first developed a redox-sensitive prodrug of EPR by conjugating Tocopherol Polyethylene Glycol Succinate (TPGS) which can form a self-assembled micellar prodrug (EPR-SS-TPPGS). Subsequently, to achieve synergistic chemotherapeutic efficacy Doxorubicin (Dox) was co-loaded into the EPR-SS-TPGS micelles where the system is disrupted in a tumor redox environment and co-delivers Dox and EPR in a ratiometric manner. We then employed TPGS conjugated vitamin-B6 as a targeting moiety and prepared the mixed micelles to facilitate VTC receptor-mediated uptake. The encapsulation of Dox and EPR with the developed prodrug approach showed significant synergies with increased intracellular accumulation and redox triggered release in MDA-MB-231 and 4T1 cell lines leading to superior cell cycle arrest, mitochondrial membrane potential, and apoptosis. Prolonged circulation half-life and tumor site bioavailability were achieved for both the drugs with the developed approach. Surprisingly, EPR and Dox combination significantly down-regulated the CD44 receptor expression which is the main contributing factor of tumor metastasis. Furthermore, in vivo evaluation demonstrated a significant reduction in Dox-induced cardiotoxicity. In summary, this nanoencapsulation paradigm of AR inhibitors with chemotherapeutic agents lays the foundation of new opportunities in combination chemotherapy.

Hyperglycemia invoke number of pathways resulting in development of diabetic retinopathy (DR), including protein kinase C activation, increased expression of VEGF, advanced glycation end product (AGEs) formation and activation of polyol pathway, among which the pathophysiology of aldose reductase (ALR2) of the polyol pathway is evident by more than a decade of research. Subtle involvement of ALR2 in invoking various pathways of diabetic complications has caused an increase in attention towards the identification of novel aldose reductase inhibitors (ARIs). Numerous ARIs of different classes were employed in the treatment of diabetic complications initially, but few came into light as drugs. Though no ALR2 inhibitor has been used for the treatment or control of DR, Epalrestat has been used worldwide for treating diabetic neuropathy. This review critically analyses different treatments available for diabetic retinopathy, their limitations and the importance of the development of novel inhibitors of ALR2 that could prevent progression of DR, by causing a direct or indirect effect on controlling factors associated with DR.

Aldose reductase (AR) is the key enzyme of the polyol pathway, which plays an important role in the pathogenesis of diabetic complications. AR inhibitors can be used as an important strategy in the treatment of diabetic complications. The aim of the present study was to investigate effect of different fractions of Salvia officinalis on the bovine lens aldose reductase activity. For this purpose, the phenolic and flavonoid contents, IC50 values of different fractions of the S. officinalis to neutralize the DPPH free radicals were first measured. Then, attempts were made to investigate the effect of these fractions on the AR enzyme activity. Results indicated that ethyl acetate fraction had the highest of phenolic and flavonoid contents by 412.6 ± 1.55 and 372.5 ± 6.47 mg/ml, respectively. Also, the ethyl acetate fraction showed the lowest IC50 content of 1.18 μg/ml for scavenging of the free radicals and 9.25 μg/ml for the inhibition of AR activity. According to the Lineweaver–Burk plot, the ethyl acetate fraction acts as an uncompetitive enzyme inhibitor. These findings revealed that all fractions showed inhibitory effect on AR activity, where in ethyl acetate fraction it was found to be maximum which may be due to its high phenolic and flavonoid content.

Advanced glycation end-products (AGEs) are proteins or lipids glycated nonenzymatically by glucose, or other reducing sugars and their derivatives, such as glyceraldehyde, glycolaldehyde, methyloglyoxal and acetaldehyde. There are three different means of AGE formation: i) Maillard reactions, the polyol pathway and lipid peroxidation. AGEs participate in the pathological mechanisms underlying the development of several diseases, such as diabetes and its complications, retinopathy or neuropathy, neurological disorders (for example, Parkinson's disease and Alzheimer's disease), atherosclerosis, hypertension and several types of cancer. AGE levels are increased in patients with hyperglycaemia, and is likely the result of the high concentration of glycation substrates circulating in the blood. The present review summarises the formation and nomenclature of advanced glycation end-products, with an emphasis on the role of AGEs in the development of diabetes, neurological disorders, as well as in cancer and other pathologies. A particular focus is placed on the functions of toxic AGEs. Additionally, studies which have shown the cytotoxicity of glycated albumin and other AGEs are also discussed. Finally, the diagnostic relevance of AGEs as well as for targeting in therapeutic strategies are highlighted.

Aldose reductase (AR) is an NADPH-dependent oxidoreductase that is well-studied for its role in Diabetes Mellitus. Glutathione conjugated aldehydes are efficiently catalysed by AR. We have employed molecular dynamics simulations to investigate the dynamics of a glutathione analog, γ-glutamyl-S-(1,2-di-carboxyethyl)-cysteinyl-glycine (DCEG), into the binding pocket of AR. Study revealed that backbone nitrogens of Ala-299 and Leu-300 form a tiny pocket gated by thiol group of Cys-298. The glycine moiety of DCEG was able to displace the thiol group of Cys-298 to make hydrogen bond interactions with backbone of Ala-299, Leu-300, and Leu-301. This study provides the details of the dynamic interactions of DCEG in the binding pocket of AR, and shall aid in the design/discovery of differential inhibitors against AR.Communicated by Ramaswamy H. Sarma.

The over expression of aldose reductase (ALR2) in the state of hyperglycemia causes the conversion of glucose into sorbitol and initiates polyol pathway. Accumulation of sorbitol in insulin insensitive tissue like peripheral nerves, glomerulus and eyes, induces diabetic complications like neuropathy, nephropathy and retinopathy. For the treatment of diabetic complications, the inhibition of aldose reductase (ALR2) is a promising approach. A series of coumarin-based thiosemicarbazone derivatives was synthesized as potential inhibitor of aldose reductase. Compound N-(2-fluorophenyl)-2-(1-(2-oxo-2H-chromen-3-yl)ethylidene)hydrazinecarbiothioamide (3n) was found to be the most promising inhibitor of ALR2 with an IC50 in micromolar range (2.07 µM) and high selectivity, relative to ALR1. The crystal structure of ALR2 complexed with 3n explored the types of interaction pattern which further demonstrated its high affinity. Compound 3n has excellent lead-likeness, underlined by its physicochemical parameters, and can be considered as a likely prospect for further structural optimization to get a drugable molecule.

Diabetes is associated with cardiac metabolic disturbances and increased heart failure risk. Plasma fructose levels are elevated in diabetic patients. A direct role for fructose involvement in diabetic heart pathology has not been investigated. The goals of this study were to clinically evaluate links between myocardial fructose and sorbitol (a polyol pathway fructose precursor) levels with evidence of cardiac dysfunction, and to experimentally assess the cardiomyocyte mechanisms involved in mediating the metabolic effects of elevated fructose. Fructose and sorbitol levels were increased in right atrial appendage tissues of type 2 diabetic patients (2.8- and 1.5-fold increase respectively). Elevated cardiac fructose levels were confirmed in type 2 diabetic rats. Diastolic dysfunction (increased E/e’, echocardiography) was significantly correlated with cardiac sorbitol levels. Elevated myocardial mRNA expression of the fructose-specific transporter, Glut5 (43% increase), and the key fructose-metabolizing enzyme, Fructokinase-A (50% increase) was observed in type 2 diabetic rats (Zucker diabetic fatty rat). In neonatal rat ventricular myocytes, fructose increased glycolytic capacity and cytosolic lipid inclusions (28% increase in lipid droplets/cell). This study provides the first evidence that elevated myocardial fructose and sorbitol are associated with diastolic dysfunction in diabetic patients. Experimental evidence suggests that fructose promotes the formation of cardiomyocyte cytosolic lipid inclusions, and may contribute to lipotoxicity in the diabetic heart.

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

Diabetic nephropathy (DN) is resulted from activations of polyol pathway and oxidative stress by abnormal metabolism of glucose, and no specific medication is available. We designed a novel class of benzoxazolone derivatives, and a number of individuals were found to have significant antioxidant activity and inhibition of aldose reductase of the key enzyme in the polyol pathway. The outstanding compound (E)-2-(7-(4-hydroxy-3-methoxystyryl)-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid was identified to reduce urinary proteins in diabetic mice suggesting an alleviation in the diabetic nephropathy, and this was confirmed by kidney hematoxylin-eosin staining. Further investigations showed blood glucose normalization, declined in the polyol pathway and lipid peroxides, and raised glutathione and superoxide dismutase activity. Thus, we suggest a therapeutic function of the compound for DN which could be attributed to the combination of hypoglycemic, aldose reductase inhibition and antioxidant.

Pancreatic β-cells become irreversibly damaged by long-term exposure to excessive glucose concentrations and lose their ability to carry out glucose stimulated insulin secretion (GSIS) upon damage. The β-cells are not able to control glucose uptake and they are therefore left vulnerable for endogenous toxicity from metabolites produced in excess amounts upon increased glucose availability. In order to handle excess fuel, the β-cells possess specific metabolic pathways, but little is known about these pathways. We present a study of β-cell metabolism under increased fuel pressure using a stable isotope resolved NMR approach to investigate early metabolic events leading up to β-cell dysfunction. The approach is based on a recently described combination of 13C metabolomics combined with signal enhanced NMR via dissolution dynamic nuclear polarization (dDNP). Glucose-responsive INS-1 β-cells were incubated with increasing concentrations of [U-13C] glucose under conditions where GSIS was not affected (2–8 h). We find that pyruvate and DHAP were the metabolites that responded most strongly to increasing fuel pressure. The two major divergence pathways for fuel excess, the glycerolipid/fatty acid metabolism and the polyol pathway, were found not only to operate at unchanged rate but also with similar quantity.

Hyperglycemia is a key determinant for development of diabetic retinopathy (DR). Inadequate glycemic control exacerbates retinopathy, while normalization of glucose levels delays its progression. In hyperglycemia, hexokinase is saturated and excess glucose is metabolized to sorbitol by aldose reductase via the polyol pathway. Therapies to reduce retinal polyol accumulation for the prevention of DR have been elusive due to low sorbitol dehydrogenase levels in the retina and inadequate inhibition of aldose reductase. Using systemic and conditional genetic inactivation, we targeted the primary facilitative glucose transporter in the retina, Glut1, as a preventative therapeutic in diabetic male and female mice. Unlike wildtype diabetics, diabetic Glut1+/− mice did not display elevated Glut1 levels in the retina. Furthermore, diabetic Glut1+/− mice exhibited ameliorated ERG defects, inflammation and oxidative stress, which was correlated with a significant reduction in retinal sorbitol accumulation. RPE-specific reduction of Glut1 did not prevent an increase in retinal sorbitol content or early hallmarks of DR. However, like diabetic Glut1+/− mice, reduction of Glut1 specifically in retinal neurons mitigated polyol accumulation and completely prevented retinal dysfunction and the elevation of markers for oxidative stress and inflammation associated with diabetes. These results suggest that modulation of retinal polyol accumulation via Glut1 in photoreceptors can circumvent the difficulties in regulating systemic glucose metabolism and be exploited to prevent DR.SignificanceDiabetic retinopathy (DR) affects one third of diabetic patients and is the primary cause of vision loss in adults aged 20-74. While anti-VEGF and photocoagulation treatments for the late-stage vision threatening complications can prevent vision loss, a significant proportion of patients do not respond to anti-VEGF therapies and mechanisms to stop progression of early-stage symptoms remain elusive. Glut1 is the primary facilitative glucose transporter for the retina. We determined that a moderate reduction in Glut1 levels, specifically in retinal neurons, but not the RPE, was sufficient to prevent retinal polyol accumulation and the earliest functional defects to be identified in the diabetic retina. Our study defines modulation of Glut1 in retinal neurons as a targetable molecule for prevention of DR.

The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease (NAFLD), cholestasis, and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC) and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 wk either a control (CON) or high-fructose high-fat (HFF) diet with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had a decreased number of neurons and an increase in reactive astrocytes in FC tissue. There was also a decrease in one-carbon metabolites choline and betaine and a marked accumulation of bile acids, cholesteryl esters, and polyol pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test and FC levels of amyloid-β and phosphorylated Tau did not differ between diets, whereas probiotics increased amyloid-β and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.

Obesity and metabolic syndrome are strongly associated with cancer, and these disorders may share a common mechanism. Recently, fructose has emerged as a driving force to develop obesity and metabolic syndrome. Thus, we assume that fructose may be the mechanism to explain why obesity and metabolic syndrome are linked with cancer. Clinical and experimental evidence showed that fructose intake was associated with cancer growth and that fructose transporters are upregulated in various malignant tumors. Interestingly, fructose metabolism can be driven under low oxygen conditions, accelerates glucose utilization, and exhibits distinct effects as compared to glucose, including production of uric acid and lactate as major byproducts. Fructose promotes the Warburg effect to preferentially downregulate mitochondrial respiration and increases aerobic glycolysis that may aid metastases that initially have low oxygen supply. In the process, uric acid may facilitate carcinogenesis by inhibiting the TCA cycle, stimulating cell proliferation by mitochondrial ROS, and blocking fatty acid oxidation. Lactate may also contribute to cancer growth by suppressing fat oxidation and inducing oncogene expression. The ability of fructose metabolism to directly stimulate the glycolytic pathway may have been protective for animals living with limited access to oxygen, but may be deleterious toward stimulating cancer growth and metastasis for humans in modern society. Blocking fructose metabolism may be a novel approach for the prevention and treatment of cancer.

One of the major public health issues is the rising prevalence of cataracts, a primary reason for preventable blindness. The causes for the development of age-related cataracts and accelerated cataractogenesis in diabetes are multifactorial. Hence, this study was designed to examine the status and relationship between the three majorly associated molecular events, namely, oxidative stress, non-enzymatic glycation, and polyol pathway in age-related cataracts with and without diabetes. A total of 472 subjects were distributed into four groups: non-diabetic subjects with clear lens (135), diabetic subjects with clear lens (40), non-diabetic subjects with cataract (174), and diabetic subjects with cataract (123). Cataracts were graded by slit-lamp examination according to the Lens Opacities Classification System III. Age at onset of cataract, type of opacity, anthropometric measurements, and sociodemographic characteristics were recorded, and clinical profile was examined. Plasma oxidative stress markers were assessed by estimating the lipid peroxidation end product malondialdehyde, protein oxidation products protein carbonyls, and DNA oxidative damage marker 8-hydroxy-2-deoxyguanosine. Plasma advanced glycation end products index, erythrocyte aldose reductase activity, and sorbitol levels were evaluated. After adjusting for age, plasma malondialdehyde levels were significantly higher in diabetic cataracts (P 0.001) and non-diabetic cataract subjects (P 0.05), compared to non-diabetic subjects with clear lens. Plasma advanced glycation end products index was significantly higher (P 0.05) only in diabetic cataracts, but not in non-diabetic subjects with cataracts. Aldose reductase activity and sorbitol levels were significantly higher (P 0.001) in both diabetic and non-diabetic subjects with cataract compared to non-diabetic subjects with clear lens. The data indicated that plasma lipid peroxidation in age-related cataracts was independent of diabetes. An association of pronounced glycation was observed only in diabetic cataracts but not in non-diabetic cataracts and polyol flux between diabetic cataracts and non-diabetic cataracts was comparable.

The generation of Reactive Oxygen Species (ROS) and Advanced Glycation Endproducts (AGE’s) resulting from chronic tissue exposure to elevated levels of glucose has been identified as a key modulator of diabetic complications including diabetic cardiomyopathy. Abnormal activation of the polyol pathway converts excess glucose to sorbitol, generating ROS and AGEs. This conversion is catalyzed by the enzyme Aldose Reductase. Inhibition of Aldose Reductase, the rate limiting enzyme in the polyol pathway, reduces the production of sorbitol, attenuates increases in NADH, and down-regulates the synthesis of ROS. Methods and Results: Cultured human adult cells (NHK) were exposed to elevated glucose [25mM] to simulate hyperglycemic conditions in diabetic tissue in the presence/absence of Aldose Reductase inhibitor AT-001 [0.18nM]. AT-001 dose selection was based on previous dose response studies. Cytosolic oxidative stress was evaluated and quantified using dihydroethidium (DHE) staining and quantitated via colorimetric assessment. Mitochondrial-specific oxidative stress ROS levels were quantitated using MitoSOX staining. AT-001 prevented the production and accumulation of ROS as assessed by both DHE quantitation and MitoSOX staining, demonstrating effective inhibition of polyol pathway associated damage to these cells. Conclusions: AT-001 effectively prevented cellular damage caused by oxidative stress under hyperglycemic conditions warranting further investigation of AT-001 in the treatment of diabetic complications. AT-001 is currently being evaluated in a pivotal phase 2/3 study (ARISE-HF NCT 04083339) to treat diabetic cardiomyopathy and prevent progression to overt heart failure and also includes sub-analyses for retinopathy and diabetic peripheral neuropathy. Disclosure R. Perfetti: Stock/Shareholder; Self; Applied Therapeutics. G. Yepuri: None. N.A. Quadri: None. R. Ramasamy: Consultant; Self; Applied Therapeutics. A.F. Ghannam: Employee; Self; Applied Therapeutics Inc. Stock/Shareholder; Self; Sanofi US. S. Shendelman: Employee; Self; Applied Therapeutics. Stock/Shareholder; Self; Applied Therapeutics. Funding Applied Therapeutics (NCT04083339)

Background: Aldol reductase (AR) is the polyol pathway's main enzyme that portrays a crucial part in developing ‘complications of diabetes’ involving cataract, retinopathy, nephropathy, and neuropathy. These diabetic abnormalities are triggered tremendously via aggregation of sorbitol formation (catalyzed by AR) in the polyol pathway. Consequently, it represents an admirable therapeutic target and vast research was done for the discovery of novel molecules as potential AR inhibitors for diabetic complications. Objective: This review article has been planned to discuss an outline of diabetic complications, AR and its role in diabetic complications, natural compounds reported as AR inhibitors, and benefits of natural/plant derived AR inhibitors for the management of diabetic abnormalities. Results: The goal of AR inhibition remedy is to stabilize the increased flux of blood glucose and sorbitol via the ‘polyol pathway’ in the affected tissues. A variety of synthetic inhibitors of AR have been established such as tolrestat and sorbinil, but both of these face limitations including low permeability and health problems. Pharmaceutical industries and other scientists were also undertaking work to develop newer, active, and ‘safe’ AR inhibitors from natural sources. Therefore, several naturally found molecules were documented to possess a potent inhibitory action on AR activity. Conclusion: Natural inhibitors of AR appeared as harmless pharmacological agents for controlling diabetic complications. The detailed literature throughout this article shows the significance of herbal extracts and phytochemicals as prospective useful AR inhibitors in treating diabetic complications.

SummaryA major nutrient source for animals is glucose, which induces transcriptional responses that shift metabolism. Such metabolic adaptation should be appropriately scaled to the ingested glucose levels, and decoupling causes human metabolic diseases. However, the identity of the crucial sensor metabolite(s) that transmit circulating glucose levels to the transcriptional machinery remains elusive. Here we show that the polyol pathway, which converts glucose to fructose via sorbitol, is required for activation of the master metabolic regulator Mondo, theDrosophilahomologue of MondoA/ChREBP. We demonstrate that under normal nutritional conditions polyol pathway metabolites promote Mondo’s nuclear localization and cause global changes in metabolic gene expression. Polyol pathway mutants block nuclear localization of Mondo and Mondo-mediated gene expression despite intact glycolytic and pentose phosphate pathways. Our results uncover the normal physiological function of this pathway and cast a new light on the adverse effects of high fructose diets in human health.

Prolonged hyperglycemia is one of the main causes of reactive oxygen species and free radicals generation in diabetes which may affect various organs, including the eye. Oxidative damage to proteins and lipids in the eye lens could lead to cataract formation. To cope with oxidative stress, the endogenous antioxidative system may be supported by the supplementation of exogenous antioxidants. The aim of this study was to evaluate the effect of chrysin, a natural flavonoid, on oxidative stress and polyol pathway-related markers in the lenses of streptozotocin-induced type 1 male diabetic rats. Chrysin at doses of 50 and 100 mg/kg was administered by gavage for 28 days. This treatment resulted in a decrease in antioxidative enzymes activity and oxidative stress index. Moreover, chrysin administration elevated the reduced glutathione level in the lenses. A decrease in the markers linked to oxidative damage to proteins and lipids in the lenses was noted, especially after treatment with 50 mg/kg of chrysin. Neither of the chrysin doses affected glycemia-related markers in the serum or altered parameters related to the polyol pathway and advanced glycation end-products level in the lenses of diabetic rats. Upon obtaining results, it can be concluded that chrysin reveals antioxidative activity in the lenses but shows no antihyperglycemic or antiglycation properties.

Bioactive natural products are enriched with inherently immense structural diversity than synthetic compounds, continuously used as safe therapeutic agents to combat with number of deadly health ailments, and will continually play leading role in discovering new drugs. Natural bioactive agents are considered privileged structures as they have the diversity space in which chemical scaffolds embody characteristics that promote binding to multiple macromolecular targets. An analysis of the origin of the drugs that were launched in the last 25 years showed that both natural products and their derived semi-synthetic compounds composed 34% of all new chemical entities, while 18% of them were synthetic mimics of natural compounds. Long-term hyperglycemia in diabetics causes acute reversible and chronic cumulative irreversible changes, includes damage to blood vessels and peripheral nerves which eventually leads to diabetic complications such as vasculopathy, nephropathy, neuropathy, retinopathy, and cataracts; greatly increasing the risk of atherosclerosis, heart attack, stroke, blindness, amputation, and kidney failure. Aldose reductase (AR, ALR2) inhibition is the most legitimate approach for the management of diabetic complications. In hyperglycemic condition, the excess of glucose firstly enters into polyol pathway via rate-limiting enzyme AR. The present review focused on exploring the journey of natural aldose reductase inhibitors such as curcumin, quercetin, berberine, etc., and their semi synthetic analogs used for the treatment of diabetic complications including their synthetic routes, stereochemistry, proposed mechanism of action, mode of binding interactions, SAR and QSAR studies in relation to elucidate the pharmacophoric structural requisite for diabetic complication prevention potential.

Reductive stress is defined as a condition of sustained increase in cellular glutathione/glutathione disulfide and NADH/NAD+ ratios. Reductive stress is emerging as an important pathophysiological event in several diseased states, being as detrimental as is oxidative stress. Occurrence of reductive stress has been documented in several cardiomyopathies and is an important pathophysiological factor particularly in coronary artery disease and myocardial infarction. Excess activation of the transcription factor, Nrf2-the master regulator of the antioxidant response-, consequent in most cases to defective autophagy, can lead to reductive stress. In addition, hyperglycemia-induced activation of the polyol pathway can lead to increased NADH/NAD+ ratio, which might translate into increased levels of hydrogen sulfide-via enhanced activity of cystathionine β-synthase-that would fuel reductive stress through inhibition of mitochondrial complex I. Reductive stress may be either a potential weapon against cancer priming tumor cells to apoptosis or a cancer's ally promoting tumor cell proliferation and making tumor cells resistant to reactive oxygen species-inducing drugs. In non-cancer pathological states reductive stress is definitely harmful paradoxically leading to reactive oxygen species overproduction via excess NADPH oxidase 4 activity. In face of the documented occurrence of reductive stress in several heart diseases, there is much less information about the occurrence and effects of reductive stress in skeletal muscle tissue. In the present review we describe relevant results emerged from studies of reductive stress in the heart and review skeletal muscle conditions in which reductive stress has been experimentally documented and those in which reductive stress might have an as yet unrecognized pathophysiological role. Establishing whether reductive stress has a (patho)physiological role in skeletal muscle will hopefully contribute to answer the question whether antioxidant supplementation to the general population, athletes, and a large cohort of patients (e.g. heart, sarcopenic, dystrophic, myopathic, cancer, and bronco-pulmonary patients) is harmless or detrimental.