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Background: Several metabolic pathways are involved in the complications of diabetes like polyol pathway. Aldose reductase (AR) is a key enzyme in the polyol pathway, which catalyzes the conversion of glucose to sorbitol. AR inhibitors are appropriate to prevent and treat the diabetes complications. Objective: This study was designed to investigate the effect of different fractions of Teucrium polium on the AR activity. Methods: Fifty cow’s eye lenses were prepared and AR enzyme was purified according to the Hyman-Kinoshita method. The enzyme activity in the presence of the crude extract and different fractions of Teucrium polium (1, 5, 10, 20 and 100 μg/ml) was measured. In addition, IC50 content of fractions was also measured for the neutralization of DPPH free radical. Since some AR inhibitors are phenolic compounds, the phenolic and flavonoid contents have been investigated. Results: Results showed that the highest phenol and flavonoid content and the lowest IC50 value (3.67 µg/ml) for AR inhibition were related to the ethyl acetate fraction. Line weaver-Burk plot showed that ethyl acetate fraction acts as a non-competitive enzyme inhibition. Conclusion: Thus, T. polium can be proposed as a therapy to prevent or treat chronic complications of diabetes in the future.

Diabetes mellitus is one of the most widely spread non-infectious cats and dogs diseases and in modern times it is reaching epidemic levels. The purpose of the research was to determine enzymes activity, which is a marker of liver’s functional activity: alanine aminotransferase, asparagine aminotransferase, alkaline phosphatase and sorbitol dehydrogenase in cats suffering from diabetes mellitus, and another purpose was to study the dynamics of sorbitol dehydrogenase activity. Two groups of cats aged 5–7 years old (males and females) 10 cats in each group were formed for the research. A control group comprised clinically healthy animals, experimental group comprised animals diagnosed with diabetes mellitus. The results of the research showed that in cats of the experimental group the glucose content was 3.31 times as high as in cats of a control group. Fructosamine characterizes the duration of hyperglycemia and in cats diagnosed with diabetes mellitus its content overshot the control indices by 32 %, that testifies to a long-standing increase in glucose amount. Because of diabetes mellitus, water-salt metabolism is damaged, for instance blood osmolality is increased. The determination of enzymes activity showed that transaminase activity doubled, whereas the alkaline phosphatase activity increased by 25 %. The concentration of total bilirubin increased more than three-fold as compared to the control. The sorbitol dehydrogenase activity in cats diagnosed with diabetes mellitus was in 2.25 times higher as compared to the animals in a control group. The activity of this enzyme, contrary to transaminase activity, is increased during the first days after hepatic dysfunction symptoms. Thus, in cats diagnosed with diabetes mellitus, liver function abnormality is developed which is manifested in activity changes of alanine aminotransferase, asparagine aminotransferase, alkaline phosphatase in the increase in bilirubin concentration as well as in the increase of sorbitol dehydrogenase activity. This enzyme is a valuable biochemical marker of liver function abnormality on the early stages of pathology development.

Elevated blood lactate levels are frequently found in critically ill patients and thought to result from tissue hypoperfusion and cellular oxygen shortage. Considering the close relationship between immune cell function and intracellular metabolism, lactate is more than a glycolytic waste molecule but able to regulate the immune response. Our aim was to elucidate the temporal and mechanistic effect of extracellular lactate on monocytes. To this end, primary human monocytes and the human monocytic cell line MonoMac6 were stimulated with various toll-like-receptor agonists after priming with Na-L-lactate under constant pH conditions. As readout, cytokine production was measured, real-time assessment of intracellular energy pathways was performed, and intracellular metabolite concentrations were determined. Irrespective of the immunogenic stimulus, short-term Na-lactate-priming strongly reduced cytokine production capacity. Lactate and hexoses accumulated intracellularly and, together with a decreased glycolytic flux, indicate a lactate-triggered impairment of glycolysis. To counteract intracellular hyperglycemia, glucose is shunted into the branching polyol pathway, leading to sorbitol accumulation. In contrast, long-term priming with Na-L-lactate induced cellular adaption and abolished the suppressive effect. This lactate tolerance is characterized by a decreased cellular respiration due to a reduced complex-I activity. Our results indicate that exogenous lactate shapes monocyte function by altering the intracellular energy metabolism and acts as a metabolic checkpoint of monocyte activation.

Water-soluble pentaamino acid fullerene (C60) derivatives (PFD) are promising nanomaterials with a wide range of biomedical applications. The present study has shown that PFD-7 competitively inhibits aldose reductase and sorbitol dehydrogenase, enzymes of the polyol pathway of glucose metabolism, which are known to be associated with diabetic complications. Treatment with PFD-7 was associated with a decrease in blood glucose level and improvement pancreas and liver morphology in rats with type 2 diabetes mellitus (induced by a high fat diet and streptozotocin). The data obtained indicating the ability of pentaamino acid fullerene (C60) derivatives to exhibit a pronounced antidiabetic effect. Thus, PFD-7 may be considered to contribute significantly to treatment of type 2 diabetes mellitus and diabetic complications. [ABSTRACT FROM AUTHOR]

Objective: NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity. Methods: To test this, we utilized an integrated transcriptomic and metabolomic approach to assess diabetogenic changes in the livers of wild type, Nrf2−/−, p62−/−, or Nrf2−/−; p62−/− mice exposed to arsenic in the drinking water for 20 weeks. Results: In contrast to canonical oxidative/electrophilic activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. This p62- and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis occurs through the upregulation of four novel NRF2 target genes, ketohexokinase (Khk), sorbitol dehydrogenase (Sord), triokinase/FMN cyclase (Tkfc), and hepatocyte nuclear factor 4 (Hnf4A). Conclusion: We demonstrate that NRF2 and p62 are essential for arsenic-mediated insulin resistance and glucose intolerance, revealing a pro-diabetic role for prolonged NRF2 activation in arsenic diabetogenesis.

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. [ABSTRACT FROM AUTHOR]

Lactate, primarily produced by the gut microbiota, performs as a necessary “information transmission carrier” between the gut and the microbiota. To investigate the role of lactate in the gut epithelium cell–microbiota interactions as a metabolic signal, we performed a combinatory, global, and unbiased analysis of metabolomic and transcriptional profiling in human colon epithelial cells (Caco-2), using a lactate treatment at the physiological concentration (8 mM). The data demonstrated that most of the genes in oxidative phosphorylation were significantly downregulated in the Caco-2 cells due to lactate treatment. Consistently, the levels of fumarate, adenosine triphosphate (ATP), and creatine significantly decreased, and these are the metabolic markers of OXPHOS inhibition by mitochondria dysfunction. The one-carbon metabolism was affected and the polyol pathway was activated at the levels of gene expression and metabolic alternation. In addition, lactate significantly upregulated the expressions of genes related to self-protection against apoptosis. In conclusion, lactate participates in gut–gut microbiota communications by remodeling the metabolomic and transcriptional signatures, especially for the regulation of mitochondrial function. This work contributes comprehensive information to disclose the molecular mechanisms of lactate-mediated functions in human colon epithelial cells that can help us understand how the microbiota communicates with the intestines through the signaling molecule, lactate.

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux via aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux via AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the ALD2 (human AR gene) is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes.

Diabetes is a leading cause of cardiovascular morbidity and mortality. Despite numerous treatments for cardiovascular disease (CVD), for patients with diabetes, these therapies provide less benefit for protection from CVD. These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify especially as the diabetes epidemic continues to expand. In this context, high levels of blood glucose stimulate the flux via aldose reductase (AR) pathway leading to metabolic and signaling changes in cells of the cardiovascular system. In animal models flux via AR in hearts is increased by diabetes and ischemia and its inhibition protects diabetic and non-diabetic hearts from ischemia-reperfusion injury. In mouse models of diabetic atherosclerosis, human AR expression accelerates progression and impairs regression of atherosclerotic plaques. Genetic studies have revealed that single nucleotide polymorphisms (SNPs) of the ALD2 (human AR gene) is associated with diabetic complications, including cardiorenal complications. This Review presents current knowledge regarding the roles for AR in the causes and consequences of diabetic cardiovascular disease and the status of AR inhibitors in clinical trials. Studies from both human subjects and animal models are presented to highlight the breadth of evidence linking AR to the cardiovascular consequences of diabetes. [ABSTRACT FROM AUTHOR]

Diabetes is a metabolic disease affecting many tissues and organs. The main etiological factor for diabetic complications is hyperglycemia and subsequent pathologies, such as oxidative stress. One of the organs susceptible to the development of diabetic complications is the eye with all of its elements, including the lens. The aim of this study was to evaluate the effect of silymarin, an extract obtained from milk thistle fruit husks, on the oxidative stress markers in the lenses of type 1 diabetic rats. The study was performed on male rats in which type 1 diabetes was induced with 60 mg/kg streptozotocin injection. Diabetic animals were treated via an intragastric tube with silymarin at 50 and 100 mg/kg doses for four weeks. Multiple oxidative stress and polyol pathway-related parameters were measured in the lenses, and auxiliary biochemical tests in the serum were conducted. Diabetes induced severe pathological changes both in the lenses and the serum, and silymarin counteracted several of them. Nevertheless, the qualitative analyses encompassing all tested parameters indicate that silymarin slightly improved the overall state of diabetic animals. Upon the obtained results, it can be concluded that silymarin reveals a faint positive effect on the lenses in type 1 diabetic rats.

Background: One of the largest problems for global public health is diabetes mellitus (DM) and its micro and macrovascular consequences. Although prevention, diagnosis, and treatment have generally improved, its incidence is predicted to keep rising over the coming years. Due to the intricacy of the molecular mechanisms, which include inflammation, oxidative stress, and angiogenesis, among others, discovering treatments to stop or slow the course of diabetic complications is still a current unmet need., Methods: The pathogenesis and development of diabetic neuropathies may be explained by a wide variety of molecular pathways, hexosamine pathways, such as MAPK pathway, PARP pathway, oxidative stress pathway polyol (sorbitol) pathway, cyclooxygenase pathway, and lipoxygenase pathway. Although diabetic neuropathies can be treated symptomatically, there are limited options for treating the underlying cause., Result: Various pathways and screening models involved in diabetic neuropathies are discussed, along with their possible outcomes. Moreover, both medicinal and non-medical approaches to therapy are also explored., Conclusion: This study highlights the probable involvement of several processes and pathways in the establishment of diabetic neuropathies and presents in-depth knowledge of new therapeutic approaches intended to stop, delay, or reverse different types of diabetic complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Retinopathy is one of the micro vascular complications of diabetes and can also be observed in pre-diabetic state. However, there are only limited studies available on the pathophysiology of retinopathy in pre-diabetic state and its preventive strategies. In this study, we investigated the retinal functional, structural and molecular alterations using high fructose (HF) induced pre-diabetic rat model and also the protective role of garlic. Feeding of HF to Wistar NIN (WNIN) rats had developed insulin resistance (IR) and impaired glucose tolerance (IGT) by three months, while retinal functional abnormalities by ten months as evidenced by decrease of Electroretinogram (ERG) scotopic, photopic b-wave amplitudes, oscillatory potentials (OPs) when compared to controls. Supplementation of garlic (3%) to HF+G group rats had marginally protected these changes. Elevated expression of glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), aldose reductase (AR) and decreased rhodopsin (Rho) in HF group rats as evidenced by immunohistochemistry, immunoblot methods, which were further supported by gene expression studies, indicate the initiation of retinal abnormalities. Increased immunefluorescence signal of carboxymethyl lysine (CML-KLH) and 4-hydroxynanoenol (4-HNE) in retina of HF group rats indicate the association of glycation and oxidative stress, respectively. Early intervention of garlic to HF+G group rats attenuated retinal functional, structural, and molecular abnormalities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is a painful devitalizing complication of diabetes affecting almost 20% individuals with this disease. Based on the area where neurons are mostly affected, it is categorized into four different types, proximal, peripheral, autonomic, and focal, and each type shows varying symptoms like numbness, gastric problems, heart problems, etc. Sometimes, these symptoms are mistakenly taken as those of gastric disorders, heart attack, or arrhythmia, with paying no attention to the inflamed neuronal supply in the particular area. Despite being aware of the symptoms, it is still a major challenging task for concerned endocrinologists and neurologists to diagnose it among the participants in clinics or in clinical trials. Treatment of diabetic neuropathy involves three major approaches, maintenance of the sugar level, pathogenetic treatment, and relieve of pain. Certain recommended drugs for pain relief are antidepressants (like duloxetine), GABA analogs (like gabapentin or pregabalin), and some other proposed treatments under research (like α-lipoic acid, aldose reductase inhibitors, or benfoitamine). The current drugs which are being provided for this disease are all indirectly acting and doesn't have any direct action on the neuronal part. So, currently the need for today is to provide most potent drugs or combination of drugs to relieve the pain of diabetic neuropathy individuals by acting directly on the nerves without laying any side effects. [ABSTRACT FROM AUTHOR]

We investigated the effect of curcumin on liver anti-oxidative stress in the type 1 diabetic rat model induced by streptozotocin (STZ). Experimental diabetic rats were induced by STZ intraperitoneally. All rats were fed for 21 days including three groups of control (NC), diabetic model (DC) and curcumin-treated (Cur, 1.5 g/kg by gavage). The results showed that curcumin-treatment significantly decreased the blood glucose and plasma malondialdehyde levels, but significantly increased the plasma superoxide dismutase, glutathione peroxidase and reduced glutathione levels. Curcumin treatment decreased the activity of aldose reductase, but increased the plasma glucose-6-phosphate dehydrogenase, glucose synthetase and glucose-polymerizing activities. Curcumin treatment significantly decreased the protein of protein kinase C (PKC) and poly ADP ribose polymerase (PARP) expression in the Cur group compared with the DC group. Moreover, the sorbitol dehydrogenase activity was significantly decreased and deterred glucose enters into the polyol pathway leading to an increased NADPH content in the Cur group compared with the DC group. Our data provides evidence that oxidative stress in diabetic rats may be attenuated by curcumin by inhibiting polyol pathway associated with down-regulated expression of PKC and PARP, as evidenced by both an increase the antioxidant enzymes levels and glycogen biosynthesis enzymes activities.

Background: Cataract is the opacification or optical dysfunction of the crystalline lens. Diabetes has been considered to be one of the major risk factors of cataract. Objective: The present study was designed to evaluate the anticataract activity of antioxidants such as Coleus forskohlii (CF) Briq and its phytoconstituent forskolin (FS) which were subjected to prevent cataract formation in vitro on glucose-induced cataract model. Materials and Methods: Goat lenses were incubated in Krebs-Ringer bicarbonate buffer pH 7.5 (supplemented with Taxim and streptomycin) containing 55 mM glucose (cataractogenesis) with fidarestat; CF methanolic extract; and FS at a concentration of 1 μg/mL, 100 μg/mL, and 10 μg/mL for 24 h at 37°C with 5% CO2and 95% air. Glucose-induced opacification of goat lens began 8–10 h after incubation and was complete in 24 h. Polyol (galactitol) levels in incubated lenses were estimated spectrophotometrically. Results: Cataractous lenses showed higher content of galactitol. However, lens treated with fidarestat, CF methanolic extract, and its phytoconstituent FS showed lower content of galactitol. Conclusion: CF and FS prevented the formation and progress of cataract by glucose, as evidenced by lens transparencies with photographic evaluation and lens galactitol levels. [ABSTRACT FROM AUTHOR]

Disrupted endothelial metabolism is linked to endothelial dysfunction and cardiovascular disease. Targeted metabolic inhibitors are potential therapeutics; however, their systemic impact on endothelial metabolism remains unknown. In this study, we combined stable isotope labeling with 13C metabolic flux analysis (13C MFA) to determine how targeted inhibition of the polyol (fidarestat), pentose phosphate (DHEA), and hexosamine biosynthetic (azaserine) pathways alters endothelial metabolism. Glucose, glutamine, and a four-carbon input to the malate shuttle were important carbon sources in the baseline human umbilical vein endothelial cell (HUVEC) 13C MFA model. We observed two to three times higher glutamine uptake in fidarestat and azaserine-treated cells. Fidarestat and DHEA-treated HUVEC showed decreased 13C enrichment of glycolytic and TCA metabolites and amino acids. Azaserine-treated HUVEC primarily showed 13C enrichment differences in UDP-GlcNAc. 13C MFA estimated decreased pentose phosphate pathway flux and increased TCA activity with reversed malate shuttle direction in fidarestat and DHEA-treated HUVEC. In contrast, 13C MFA estimated increases in both pentose phosphate pathway and TCA activity in azaserine-treated cells. These data show the potential importance of endothelial malate shuttle activity and suggest that inhibiting glycolytic side branch pathways can change the metabolic network, highlighting the need to study systemic metabolic therapeutic effects.

In this exploration, we assessed the antihyperglycaemic properties of methanol extract of flowers of Thunbergia mysorensis (MeT) against α-glucosidase, α-amylase and aldose reductase enzymes for the effective management of postprandial hyperglycemia. Hyperglycemia occurs when the body lacks enough insulin or is unable to correctly utilize it. MeT inhibited both the carbohydrate digestive enzymes (α-glucosidase and α-amylase) and aldose reductase, which are vital for the therapeutic control of postprandial hyperglycaemia. MeT was also found to have significant antioxidant activity. Using several spectroscopic approaches, the primary active component found in MeT was identified as gallic acid. With low Ki values, gallic acid significantly inhibited α-glucosidase (30.86 µg/mL) and α-amylase (6.50 µg/mL). Also, MeT and gallic acid both inhibited aldose reductase effectively, corresponding to an IC 50 value of 3.31 and 3.05 µg/mL. Our findings imply that the presence of polyphenol compounds (identified via HPLC analysis) is more likely to be responsible for the antihyperglycaemic role exhibited by MeT via the inhibition of α-glucosidase and the polyol pathway. Further, gallic acid interacted with the key residues of the active sites of α-glucosidase (-6.4 kcal/mol), α-amylase (-5.8 kcal/mol) and aldose reductase (-5.8 kcal/mol) as observed in the protein-ligand docking. It was also predicted that gallic acid was stable inside the binding pockets of the target enzymes during molecular dynamics simulation. Overall, gallic acid derived from MeT via bioassay-guided isolation emerges as a natural antidiabetic drug and can be taken into in vivo and clinical studies shortly.Communicated by Ramaswamy H. Sarma.

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.

Recently repeated heat stress and dehydration have been reported to cause oxidative stress and kidney damage that is enhanced by rehydrating with fructose solutions. We hypothesized that antioxidants might provide a novel way to prevent kidney damage. To test this hypothesis, mild heat stress was induced by exposing rats to 37 °C during 1 h in a closed chamber. The supplementation with water-soluble antioxidants (Antiox), ascorbic acid 1% plus N-acetyl cysteine 600 mg/L was done either in the 10% fructose 2 h rehydration fluid immediately after heat stress (Fructose 10% + Antiox), and/or in the tap water (Water + Antiox) for the remainder of the day, or in both fluids. After 4 weeks, control rats exposed to heat with fructose rehydration developed impaired renal function, tubular injury, intrarenal oxidative stress, a reduction in Nrf2-Keap1 antioxidant pathway, stimulation of vasopressin and the intrarenal polyol-fructokinase pathway. In contrast, dosing the antioxidants in the tap water (i.e., before the heat exposure and rehydration with fructose) preserved renal function, prevented renal tubule dysfunction and avoided the increase in systemic blood pressure. These effects were likely due to the amplification of the antioxidant defenses through increased Nrf2 nuclear translocation stimulated by the antioxidants and by the prevention of polyol fructokinase pathway overactivation. More studies to understand the mechanisms implicated in this pathology are warranted as there is recent evidence that they may be operating in humans as well. Image 1 • Antioxidants conferred nephroprotection in heat-induced dehydration and rehydration with fructose containing beverages. • Antioxidants activated eNOS pathway and Nrf2 nuclear translocation thus preserving antioxidant defenses. • Antioxidant prevented the overactivation of aldose reductase and fructokinase pathways. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate the aldose reductase inhibition and anti-cataract property of W. volubilis root extract in rats with streptozotocin induced diabetes mellitus. Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin at the dose of 45 mg/kg. Diabetic animals were treated with glimepiride (0.5 mg/kg) and alcohol extract at 100 and 200 mg/kg for 38 d. Lens were isolated and certain markers were estimated. Results: Treatment of diabetic animals with alcohol extract of W. volubilis root inhibited aldose reductase activity (p < 0.001) and sorbitol formation in the lens. Additionally, a reduction in the levels of MDA, GSH, SDH and LDH in extract treated groups was observed. There was an overall decrease in the severity of cataract progression. Conclusion: The result provided evidence that alcohol extract of W. volubilis root prevents the development of diabetic cataract in rats. [ABSTRACT FROM AUTHOR]

Non-enzymatic glycation of lens proteins and elevated polyol pathway in the eye lens have been the characteristic features of a diabetic condition. We have previously reported the benefits of zinc supplementation in reducing hyperglycemia and associated metabolic abnormalities and oxidative stress in diabetic rats. The current study explored whether zinc supplementation protects against cataractogenesis through modulation of glycation of lens proteins, elevated polyol pathway, oxidative stress, and proportion of different heat shock proteins in the eye lens of diabetic rats. Streptozotocin-induced diabetic rats were fed with a zinc-enriched diet (5 and 10 times of normal) for 6 weeks. Supplemental zinc alleviated the progression and maturation of diabetes-induced cataract. Zinc was also effective in preventing the reduced content of total and imbalanced proportion of soluble proteins in the lens. Supplemental zinc also alleviated cross-linked glycation and concomitant expression of the receptor of glycated products and oxidative stress indicators in the eye lens. Zinc supplementation further induced the concentration of heat shock protein in the eye lens of diabetic rats, specifically α-crystallin. Zinc supplementation counteracted the elevated activity and expression of polyol pathway enzymes and molecules in the lens. The results of this animal study endorsed the advantage of zinc supplementation in exerting the antiglycating influence and downregulating polyol pathway enzymes to defer cataractogenesis in diabetic rats. [ABSTRACT FROM AUTHOR]

In the previous study, the artichoke leaf extract showed effective inhibition of AKR1B1, the first enzyme of polyol pathway, which reduces high level of glucose to osmotically active sorbitol, important for development of chronic diabetic complications. In the present study, the effect of artichoke leaf extract and of several participating phenols (caffeic acid, chlorogenic acid, quinic acid, and luteolin) was tested on sorbitol level in rat lenses exposed to high glucose ex vivo, on cytotoxicity as well as on oxidative stress in C2C12 muscle cell line induced by high glucose in vitro. The concentration of sorbitol was determined by enzymatic analysis, the cytotoxicity was provided by WST-1 test and intracellular content of reactive oxygen species was determined by fluorescence of 2'-7'-dichlorofluorescein probe. The extract and the compounds tested showed significant protection against toxic effects of high concentration of glucose in both models. On balance, the artichoke leaf extract thus represents a prospective preventive agent of development of chronic diabetic complications, probably due to phenols content, concerning preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

The interest in fructose metabolism is based on the observation that an increased dietary fructose consumption leads to an increased risk of obesity and metabolic syndrome. In particular, obesity is a known risk factor to develop many types of cancer and there is clinical and experimental evidence that an increased fructose intake promotes cancer growth. The precise mechanism, however, in which fructose induces tumor growth is still not fully understood. In this article, we present an overview of the metabolic pathways that utilize fructose and how fructose metabolism can sustain cancer cell proliferation. Although the degradation of fructose shares many of the enzymes and metabolic intermediates with glucose metabolism through glycolysis, glucose and fructose are metabolized differently. We describe the different metabolic fates of fructose carbons and how they are connected to lipogenesis and nucleotide synthesis. In addition, we discuss how the endogenous production of fructose from glucose via the polyol pathway can be beneficial for cancer cells.

Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.

Background: The Zolfino bean is a variety of Phaseolus vulgaris, which is cultivated in a limited area of Tuscany, Italy, and is widely appreciated for its flavor and culinary uses. Objectives: A yellow Zolfino landrace cultivated in the Leccio-Reggello area was characterized and compared with three other varieties of Phaseolus vulgaris (i.e. the Borlotto, Cannellino, and Corona beans) in terms of its general features and potential as an antioxidant/anti-inflammatory agent. Design: The length, width, thickness, equatorial section surface, weight, volume, and seed coat section were measured in all the beans. The seed surface area was also estimated by an original empirical method. The ability of the different beans to interfere with the enzymes of the polyol pathway (that is, aldose reductase (AR) and sorbitol dehydrogenase) was tested using the supernatant after soaking the beans at room temperature and after thermal treatment, which simulated the bean-cooking process in a controlled fashion. Results: Concerning the general features, Zolfino was comparable with other beans, except Corona, in terms of surface–volume ratio, which possesses the lowest tegument thickness. Moreover, Zolfino appears the most effective in inhibiting AR activity. The inhibitory ability is unaffected by thermal treatment and appears to be associated with compound(s) present in the coat of the bean. Conclusions: The ability of Zolfino to inhibit AR, thus reducing the flux of glucose through the polyol pathway, highlights the features of Zolfino as a functional food, potentially useful in treating the dysfunctions linked to the hyperactivity of AR, such as diabetic complications or inflammatory responses.

Jinzi Wu,1Zhen Jin,1Hong Zheng,1,2Liang-Jun Yan1 1Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, USA; 2Department of Basic Theory of Traditional Chinese Medicine, College of Basic Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China Abstract: NAD+ is a fundamental molecule in metabolism and redox signaling. In diabetes and its complications, the balance between NADH and NAD+ can be severely perturbed. On one hand, NADH is overproduced due to influx of hyperglycemia to the glycolytic and Krebs cycle pathways and activation of the polyol pathway. On the other hand, NAD+ can be diminished or depleted by overactivation of poly ADP ribose polymerase that uses NAD+ as its substrate. Moreover, sirtuins, another class of enzymes that also use NAD+ as their substrate for catalyzing protein deacetylation reactions, can also affect cellular content of NAD+. Impairment of NAD+ regeneration enzymes such as lactate dehydrogenase in erythrocytes and complex I in mitochondria can also contribute to NADH accumulation and NAD+ deficiency. The consequence of NADH/NAD+ redox imbalance is initially reductive stress that eventually leads to oxidative stress and oxidative damage to macromolecules, including DNA, lipids, and proteins. Accordingly, redox imbalance-triggered oxidative damage has been thought to be a major factor contributing to the development of diabetes and its complications. Future studies on restoring NADH/NAD+ redox balance could provide further insights into design of novel antidiabetic strategies. Keywords: mitochondria, complex I, reactive oxygen species, polyol pathway, poly ADP ribosylation, sirtuins, oxidative stress, oxidative damage

Fructose has recently been proposed to stimulate vasopressin secretion in humans. Fructose-induced vasopressin secretion is not only postulated to result from ingestion of fructose-containing drinks but may also occur from endogenous fructose production via activation of the polyol pathway. This raises the question of whether fructose might be involved in some cases of vasopressin-induced hyponatremia, especially in situations where the cause is not fully known such as in the syndrome of inappropriate secretion of diuretic hormone (SIADH) and exercise-associated hyponatremia, which has been observed in marathon runners. Here we discuss the new science of fructose and vasopressin, and how it may play a role in some of these conditions, as well as in the complications associated with rapid treatment (such as the osmotic demyelination syndrome). Studies to test the role of fructose could provide new pathophysiologic insights as well as novel potential treatment strategies for these common conditions., (Published by Elsevier Inc.)

In this work we demonstrate that aldose reductase (AR) interacts directly with tubulin and, was subjected to microtubule formation conditions, enzymatic AR activity increased more than sixfold. Since AR interacts mainly with tubulin that has 3-nitro-tyrosine in its carboxy-terminal, we evaluated whether tyrosine and other phenolic acid derivatives could prevent the interaction tubulin/AR and the enzymatic activation. The drugs evaluated have two characteristics in common: the presence of an aromatic ring and a carboxylic substituent. The 9 drugs tested were able to prevent both the interaction tubulin/AR and the enzymatic activation. In addition, we found that the induction of microtubule formation by high concentrations of glucose and the consequent activation of AR in cultured cells can be inhibited by phenolic acid derivates that prevent the interaction tubulin/AR. These results suggest that tubulin regulates the activation of AR through a direct interaction which can be controlled with phenolic derivates of carboxylic acids. [ABSTRACT FROM AUTHOR]

Purpose and Methods: Hyperglycemia-induced osmotic and oxidative stress is thought to be involved in the pathogenesis of diabetes-related secondary complications including cataract. In continuation of our previous observation of the ameliorative influence of these spices on hyperglycemia, attendant metabolic abnormalities, and oxidative stress in tissues of diabetic rats, the beneficial influence of dietary (10%) fenugreek seeds, (3%) onion, or their combination was investigated on diabetes-induced alteration in the eye lens of streptozotocin-induced diabetic rats. Results: Animals maintained on these spices showed significantly countered oxidative stress markers (reactive oxygen species, lipid peroxidation and protein carbonyl), advanced glycation end products, and expression of their receptor in the eye lens. Increased activity of polyol pathway enzymes, their protein, and mRNA expression was significantly countered in the cataractogenic lens as a result of these dietary interventions. Altered crystallin (αA and αB) distribution profile, their expression, activity of carbohydrate metabolizing enzymes, and antioxidant status were significantly annulled by these dietary treatments. Physical and visual observation of the photomicrographs of the lenses of treated rats indicated that these dietary interventions delayed cataractogenesis in diabetic rats. Conclusions: Overall, the present investigation evidenced a beneficial modulation of the progression of cataractogenesis by dietary fenugreek seeds and onion, implicating their potential in ameliorating cataract in diabetics. [ABSTRACT FROM AUTHOR]