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Demir, Yeliz; Ardahan Üniversitesi - Nihat Delibalta Göle Meslek Yüksekokulu - Eczane Hizmetleri Bölümü - Eczane Hizmetleri Programı - Makale, Aldose reductase (AR) is the first and rate‐limiting enzyme of the polyol pathway, which converts glucose to sorbitol in an NADPH‐dependent reaction. α‐Glycosidase breaks down starch and disaccharides to glucose. Hence, inhibition of these enzymes can be regarded a considerable approach in the treatment of diabetic complications. AR was purified from sheep liver using simple chromatographic methods. The inhibitory effects of pyrazolyl–thiazoles ((3aR,4S,7R,7aS)‐2‐(4‐{1‐[4‐(4‐bromophenyl) thiazol‐2‐yl]‐5‐(aryl)‐4,5‐dihydro‐1H‐pyrazol‐3‐yl}phenyl)‐3a,4,7,7a‐tetrahydro‐1H‐ 4,7‐methanoisoindole‐1,3(2H)‐dione derivatives; 3a–i) on AR and α‐glycosidase enzymes were investigated. All compounds showed a good inhibitory action against AR and α‐glycosidase. Among these compounds, compound 3d exhibited the best inhibition profiles against AR, with a Ki value of 7.09 ± 0.19 μM, whereas compound 3e showed the lowest inhibition effects, with a Ki value of 21.89 ± 1.87 μM. Also, all compounds showed efficient inhibition profiles against α‐glycosidase, with Ki values in the range of 0.43 ± 0.06 to 2.30 ± 0.48 μM, whereas the Ki value of acarbose was 12.60 ± 0.78 μM. Lastly, molecular modeling approaches were implemented to predict the binding affinities of compounds against AR and α‐glycosidase. In addition, the ADME analysis of the molecules was performed.

Diabetic nephropathy (DN) is a chronic diabetic microvascular complication. Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel inhibitor of AR. The present study aimed at exploring the effects of WJ-39 in DN. DN was induced in rats by injecting 30 mg/kg streptozotocin (STZ). After 14 weeks, WJ-39 (10, 20, and 40 mg/kg) was intragastrically administered to the rats for 12 weeks. Treatment with WJ-39 significantly inhibited AR activation and ameliorated renal dysfunction and fibrosis in DN rats. WJ-39 reduced oxidative stress in the kidneys of DN rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. WJ-39 suppressed the activation of the nuclear factor-kappa B (NF-κB) pathway and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the secretion of inflammatory factors. Rat mesangial cells (RMCs) were cultured under hyperglycemic conditions. WJ-39 abrogated the high glucose- (HG-) induced, excessive production of reactive oxygen species (ROS) and inflammatory factors. However, transfection with Nrf2 small interfering RNA abolished the effects of WJ-39. WJ-39 also blocked the transforming growth factor-β1/Smad pathway to reduce the production of glomerular extracellular matrix proteins, ultimately reducing fibrogenesis in DN. Our results show that WJ-39 ameliorated renal injury in DN rats, and its effects on oxidative stress and inflammation were associated with the activation of Nrf2 signaling. Thus, WJ-39 and its mechanism of amelioration of renal lesions in DN rats by reducing renal inflammation, oxidative stress, and fibrosis injury could be an effective strategy for the treatment of DN.

Diabetes mellitus is constantly increasing worldwide. Vascular complications are the most common in the setting of long-standing disease, claiming the greatest burden in terms of morbidity and mortality. Glucotoxicity is involved in vascular damage through different metabolic pathways, such as production of advanced glycation end-products, activation of protein kinase C, polyol pathway activation and production of reactive oxygen species. Vascular complications can be classified according to the calibre of the vessels involved as microvascular (such as diabetic retinopathy, nephropathy and neuropathy) or macrovascular (such as cerebrovascular, coronary and peripheral artery disease). Previous studies showed that the severity of vascular complications depends on duration and degree of hyperglycaemia and, as consequence, early trials were designed to prove that intensive glucose control could reduce the number of vascular events. Unfortunately, results were not as satisfactory as expected. Trials showed good results in reducing incidence of microvascular complications but coronary heart diseases, strokes and peripheral artery diseases were not affected despite optimal glycemia control. In 2008, after the demonstration that rosiglitazone increases cardiovascular risk, FDA demanded stricter rules for marketing glucose-lowering drugs, marking the beginning of cardiovascular outcome trials, whose function is to demonstrate the cardiovascular safety of anti-diabetic drugs. The introduction of new molecules led to a change in diabetes treatment, as some new glucose-lowering drugs showed not only to be safe but also to ensure cardiovascular benefit to diabetic patients. Empaglifozin, a sodium-glucose cotransporter 2 inhibitor, was the first molecule to show impressing results, followed on by glucagon-like peptide 1 receptor agonists, such as liraglutide. A combination of anti-atherogenic effects and hemodynamic improvements are likely explanations of the observed reduction in cardiovascular events and mortality. These evidences have opened a completely new era in the field of glucose-lowering drugs and of diabetes treatment in particular with respect to vascular complications.

The prevalence of diabetes is continuously increasing in the recent decades. Persistent hyperglycaemia, hyperinsulinemia and the subsequent oxidative stress result in diabetic complications, primarily categorized as microvascular (nephropathy, retinopathy and neuropathy) and macrovascular (cardiomyopathy) complications. The complications are prevalent in both type 1 and type 2 diabetic patients. Polyol pathway, elevated AGE production, PKC activation and hexosamine pathway are indeed the critical pathways involved in the progression of diabetic complications. Silent information regulator 2 or SIR2 or more commonly known as sirtuins are NAD+ dependent histone deacetylase. SIRT1, a member of the sirtuin family has been extensively studied for its role in lifespan extension and needs to be explored for its beneficial effects in diabetic complications. Moreover, it is also known to regulate the activity of other proteins and transcription factors. One such substrate of SIRT1 is FOXOs transcription factor which has gained much attention as the mediator of various cellular processes such as cell cycle arrest and proliferation, DNA repair and metabolism. It has been reported that SIRT1 regulates the activity of FOXOs, whereas few recent advances also suggest a role FOXOs in governing the activity of SIRT1, which permits for a crosstalk between SIRT1 and FOXOs. Therefore, the focus of the present review is to describe and explore the interaction between SIRT1 and FOXOs, predominantly FOXO1 and FOXO3 and to understand the underlying mechanism of SIRT1-FOXOs in controlling and alleviating diabetic complications. Thus, this crosstalk suggests that SIRT1 and FOXOs may serve as potential therapeutic targets in treating diabetic complications.

Diabetic retinopathy (DR) remains the leading cause of blindness in working-aged adults around the world. The proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) are the severe vision threatening stages of the disorder. Although, a huge body of research exists in elaborating the pathological mechanisms that lead to the development of DR, the certainty and the correlation amongst these pathways remain ambiguous. The complexity of DR lies in the multifactorial pathological perturbations that are instrumental in both the disease development and its progression. Therefore, a holistic perspective with an understanding of these pathways and their correlation may explain the pathogenesis of DR as a unifying mechanism. Hyperglycemia, oxidative stress and inflammatory pathways are the crucial components that are implicated in the pathogenesis of DR. Of these, hyperglycemia appears to be the initiating central component around which other pathological processes operate. Thus, this review discusses the role of hyperglycemia, oxidative stress and inflammation in the pathogenesis of DR, and highlights the cross-talk amongst these pathways in an attempt to understand the complex interplay of these mechanisms. Further, an effort has been made to identify the knowledge gap and the key players in each pathway that may serve as potential therapeutic drug targets.

Over activated molecular target ALR2 of polyol pathway and oxidative stress are two well established pathological indicators in diabetic complications. In present study, mutual prodrugs of Epalrestat and natural product based antioxidants were designed, synthesized and evaluated. In silico techniques such as molecular dynamic simulations and quantum mechanical approaches, considering human esterase enzyme (hCE1) as the site of hydrolytic cleavage were employed in designing of these mutual prodrugs. Geometrical parameters (distance and Burgi-Dunitz angle favorable for nucleophilic attack) and quantum mechanical parameters (HOMO-LUMO energy gap), which govern the hydrolytic cleavage of ester prodrugs by esterase enzyme were calculated. Further, on the basis of in silico analysis, mutual prodrugs were synthesized and considering the values of in silico parameters, EPL-GUA (3g) was evaluated for its in vivo antioxidant activity. Results suggested that 3g possess significant antioxidant activity intermediary to control and Epalrestat. Thus, this study has concluded that these mutual prodrugs could be optimized to develop molecules for the management of diabetic complications.

Diabetic complications are among the largely exigent health problems currently. Cardiovascular complications, including diabetic cardiomyopathy (DCM), account for more than 80% of diabetic deaths. Investigators are exploring new therapeutic targets to slow or abate diabetes because of the growing occurrence and augmented risk of deaths due to its complications. Research on rodent models of type 1 and type 2 diabetes mellitus, and the use of genetic engineering techniques in mice and rats have significantly sophisticated for our understanding of the molecular mechanisms in human DCM. DCM is featured by pathophysiological mechanisms that are hyperglycemia, insulin resistance, oxidative stress, left ventricular hypertrophy, damaged left ventricular systolic and diastolic functions, myocardial fibrosis, endothelial dysfunction, myocyte cell death, autophagy, and endoplasmic reticulum stress. A number of molecular and cellular pathways, such as cardiac ubiquitin proteasome system, FoxO transcription factors, hexosamine biosynthetic pathway, polyol pathway, protein kinase C signaling, NF-κB signaling, peroxisome proliferator-activated receptor signaling, Nrf2 pathway, mitogen-activated protein kinase pathway, and micro RNAs, play a major role in DCM. Currently, there are a few drugs for the management of DCM and some of them have considerable adverse effects. So, researchers are focusing on the natural products to ameliorate it. Hence, in this review, we discuss the pathogical, molecular, and cellular mechanisms of DCM; the current diagnostic methods and treatments; adverse effects of conventional treatment; and beneficial effects of natural product-based therapeutics, which may pave the way to new treatment strategies. Graphical Abstract.

Background: Recent epidemiological and experimental studies have shown that obesity is a major risk factor for Colorectal Cancer (CRC). Regular intake of high fat-containing diet can promote obesity and metabolic syndrome by increasing the insulin resistance and inflammatory response which contribute to carcinogenesis. Previously, we have shown that inhibition of polyol pathway enzyme aldose reductase (AR) prevents carcinogens- and inflammatory growth factorsinduced CRC. However, the effect of AR inhibition on a high-fat diet (HFD)-induced formation of intestinal polyps in Apc-deficient Min (multiple intestinal neoplasia; ApcMin/+) mice is not known. Methods: We examined the effect of AR inhibitor, fidarestat on the HFD-induced formation of preneoplastic intestinal polyps in ApcMin/+ mice which is an excellent model of colon cancer. Results: APCMin/+ mice fed for 12 weeks of HFD caused a significant increase in the formation of polyps in the small and large intestines and fidarestat given along with the HFD prevented the number of intestinal polyps. Fidarestat also decreased the size of the polyps in the intestines of HFDtreated APC Min mice. Further, the expression levels of beta-catenin, PCNA, PKC-β2, P-AKT, Pp65, COX-2, and iNOS in the small and large intestines of HFD-treated mice significantly increased, and AR inhibitor prevented it. Conclusion: Our results thus suggest that fidarestat could be used as a potential chemopreventive drug for intestinal cancers due to APC gene mutations.

Aldose reductase, the pivotal enzyme in the polyol pathway, has been widely investigated as an enzyme critically involved in the onset and progression of various pathologies associated with diabetes mellitus. Investigation of the inhibitory effect of tara [Caesalpinia spinosa (Molina) Kuntze] pods extract on aldose reductase revealed that its n-butanol fraction exhibits excellent aldose reductase inhibitory activity in vitro and ex vivo. Methyl gallate and pistafolin B were isolated from the n-butanol fraction of the tara pod methanolic extract as the main contributors for its aldose reductase inhibition, guided by affinity-based ultrafiltration-high performance liquid chromatography, with pistafolin B being the more potent inhibitor of the two. In vitro and in silico results demonstrated that pistafolin B is a mixed-type inhibitor that can bind to the aldose reductase active site rapidly, preventing substrate access and product formation (IC50, 0.198 mM; Ki, 0.34 mM). Ex vivo experiments indicated that pistafolin B can penetrate the eye lens and successfully inhibit aldose reductase under hyperglycaemic conditions, thus preventing the accumulation of sorbitol and the subsequent osmotic stress.

Diabetic retinopathy (DR) is a retinal disease which is one of the most severe complications occuring due to diabetes mellitus and is a major cause of blindness. Patients who have diabetes mellitus for number of years develop characteristic group of lesions in the retina which leads to Diabetic retinopathy. It is a multifactorial condition occuring due to complex cellular interactions between biochemical and metabolic abnormalities taking place in all retinal cells. Considerable research efforts in the past 20 years have suggested that the microvasculature of the retina responds to hyperglycemia through a number of biochemical changes, which includes polyol pathway, protein kinase C activation, upregulation of advanced glycation end products formation and renin angiotensin system activation. Various previous studies had suggest that interaction of these biochemical changes may cause a cascade of events, such as apoptosis, oxidative stress, inflammation and angiogenesis which can lead to the damage of a diabetic retina, causing DR. This highlights that oxidative stress, inflammation, angiogenesis-related factors triggers the occurrence of retinal complication in diabetes are highlighted. Keywords: Diabetic retinopathy, Oxidative stress, Inflammation, Angiogenesis

We have a large body of evidence showing that hyperglycemia is a cardiovascular risk factor and that its reduction decreases the risk for cardiovascular events. Indeed, epidemiological studies have clearly shown that hyperglycemia is a strong and independent factor for cardiovascular disease. In addition, we have many pathophysiological studies demonstrating the direct role of hyperglycemia in the development of atherosclerosis. Hyperglycemia, by stimulating protein kinase C, increases the production of pro-inflammatory cytokines, of adhesion molecules and of endothelin-1 and, by stimulating the polyol pathway, promotes the oxidative stress. Furthermore, chronic hyperglycemia leads to the accumulation of advanced glycation end-products that modify the structure of the arterial wall and, as a consequence, will increase the risk for the development of atherosclerosis. Moreover, prolonged intervention studies have shown that reduction of hyperglycemia is associated with a significant decrease in the risk for major cardiovascular events. Thus, hyperglycemia is a cardiovascular risk factor which is characterized by the fact that it induces profound modifications of the arterial wall and that it is necessary to correct hyperglycemia during enough time to obtain a cardiovascular benefit.

Novel derivatives of spiroimidazolidinedione were synthesized and evaluated as hypoglycemic agents through binding to sulfonylurea receptor 1 (SUR1) in pancreatic beta-cells. Their selectivity index was calculated against both aldehyde reductase (ALR1) and aldose reductase (ALR2). Aldehyde reductase is a key enzyme in the polyol pathway that is involved in the etiology of the secondary diabetic complications. All structures were confirmed by microanalysis and by IR, 1H NMR, 13C NMR and EI-MS spectroscopy. The investigated compounds were subjected to molecular docking and an in silico prediction study to determine their free energy of binding (ΔG) values and predict their physicochemical properties and drug-likeness scores. Compound 1′-(5-chlorothiophene-2-ylsulfonyl)spiro[cyclohexane-1,5′-imidazolidine]-2′,4′-dione showed IC50 0.47 µM and 79% reduction in blood glucose level with a selectivity index 127 for ALR2.

There has been an alarming increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. Uncontrolled T2DM can lead to alterations in the immune system, increasing the risk of susceptibility to infections such as Mycobacterium tuberculosis (M. tb). Altered immune responses could be attributed to factors such as the elevated glucose concentration, leading to the production of Advanced Glycation End products (AGE) and the constant inflammation, associated with T2DM. This production of AGE leads to the generation of reactive oxygen species (ROS), the use of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via the Polyol pathway, and overall diminished levels of glutathione (GSH) and GSH-producing enzymes in T2DM patients, which alters the cytokine profile and changes the immune responses within these patients. Thus, an understanding of the intricate pathways responsible for the pathogenesis and complications in T2DM, and the development of strategies to enhance the immune system, are both urgently needed to prevent co-infections and co-morbidities in individuals with T2DM.

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.

Objective Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. Materials and Methods Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. Results Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD+ level with the increase of renal hypoxia-inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. Conclusion These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD.

Traditionally, the leading hypothesis regarding the development of obesity involves caloric imbalance, whereby the amount of calories consumed exceeds the amount of calories burned which causes obesity. Another hypothesis for why we get fat has surfaced in the last decade which is the idea that the overconsumption of added sugars and refined carbohydrates induce insulin resistance and high insulin levels causing obesity. While insulin is a fat-storing hormone, this hypothesis does not explain visceral adiposity, or why certain people are found to have fat stored in and around their organs. We propose a new mechanism for body fattening, particular visceral adiposity. This hypothesis involves the overconsumption of fructose, which leads to inflammation in all cells that metabolize it rapidly. When fructose is metabolized in subcutaneous adipocytes, the subsequent inflammation leads to an increase in intracellular cortisol in order to help squelch the inflammation. Unfortunately, the increase in intracellular cortisol leads to an increased flux of fatty acids out of the subcutaneous adipocytes allowing more substrate for fat storage into visceral fat tissue. Moreover fructose-induced inflammation in the liver also leads to increased intracellular cortisol via an upregulation of 11-B hydroxysteroid dehydrogenase type 1 causing increased fat storage in the liver (i.e., fatty liver). In essence, the fructose-induced inflammatory cortisol response causes "thin on the outside, fat on the inside" (TOFI). Furthermore, fructose in the brain, either from fructose uptake via the blood brain barrier or endogenous formation from glucose via the polyol pathway stimulates an increased release of cortisol causing hepatic gluconeogenesis leading to overall insulin resistance and further body fattening. This review paper will discuss in detail the hypothesis that fructose-induced inflammation and cortisol activation causes visceral adiposity.

Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFb signature genes. Excess glucose was found to promote EMT through autocrine TGFb stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target. This work was supported by the Interdisciplinary Center for Clinical Research (IZKF) of the University of Erlangen-Nuremberg, the Deutsche Krebshilfe grant number 70112536, the IALSC Lung Cancer Young Investigator Award (to P. Ceppi), and by the Clinical Research GroupKFO262 funded by the German Research Foundation. This work was partially presented at the American Association for Cancer Research 2017 annual meeting. Special thanks to Dr. H. Wurdak (University of Leeds) for critical discussion.

Aldose reductase (AR) is involved in the pathogenesis of complications in diabetes. In this study, the enzymatic properties of AR isolated from various sources and a recombinant human AR (rh-AR) were analyzed in detail. The sensitivity of different forms of AR to several AR inhibitors (ARIs) was compared. Our findings enabled us to propose that human AR should be used as the target enzyme in the development of ARIs. An enzyme-linked immunosorbent assay (ELISA) for human AR which employed monoclonal antibodies against rh-AR was created, and this method was used to demonstrate the distribution of AR in human tissues. AR was widely distributed in various organs and blood cell components. The levels of erythrocyte AR (e-AR) were 10.1±1.9 ng/mg Hb and 10.5±3.0 ng/mg Hb in healthy volunteers and diabetic patients, respectively, and thus there was no significant difference between them. The e-AR levels of diabetic patients were assayed using the ELISA developed to investigate the potential correlation between AR levels and the onset of diabetic complications. There were significant correlations between the incidence of diabetic neuropathy and e-AR levels in patients with disease duration of less than 10 years, and between the incidence of diabetic retinopathy and e-AR levels in patients with disease duration of 10-20 years. Our results suggest that measurement of e-AR levels in patients could help optimize drug therapy with ARIs and be a useful method to predict the onset of complications due to the upregulation of the polyol pathway.

Vascular endothelium plays a role in capillary transport of nutrients and drugs and regulates angiogenesis, homeostasis, as well as vascular tone and permeability as a major regulator of local vascular homeostasis. The present study has been designed to investigate the role of endothelium in metabolic disorders. The endothelium maintains the balance between vasodilatation and vasoconstriction, procoagulant and anticoagulant, prothrombotic and antithrombotic mechanisms. Diabetes mellitus causes the activation of aldose reductase, polyol pathway and advanced glycation-end-product formation that collectively affect the phosphorylation status and expression of endothelial nitric oxide synthatase (eNOS) and causes vascular endothelium dysfunction. Elevated homocysteine levels have been associated with increase in LDL oxidation, generation of hydrogen peroxides, superoxide anions that increased oxidative degradation of nitric oxide. Hyperhomocysteinemia has been reported to increase the endogenous competitive inhibitors of eNOS viz L-N-monomethyl arginine (L-NMMA) and asymmetric dimethyl arginine (ADMA) that may contribute to vascular endothelial dysfunction. Hypercholesterolemia stimulates oxidation of LDL cholesterol, release of endothelins, and generation of ROS. The increased cholesterol and triglyceride level and decreased protective HDL level, decreases the activity and expression of eNOS and disrupts the integrity of vascular endothelium, due to oxidative stress. Hypertension also stimulates release of endothelins, vasoconstrictor prostanoids, angiotensin II, inflammatory cytokines, xanthine oxidase and, thereby, reduces bioavailability of nitric oxide. Thus, the cellular and molecular mechanisms underlying diabetes mellitus, hyperhomocysteinemia, hypercholesterolemia hypertension and hyperuricemia leads to an imbalance of phosphorylation and dephosphorylation status of lipid and protein kinase that cause modulation of vascular endothelial L-arginine/nitric oxide synthetase (eNOS), to produce vascular endothelium dysfunction.

The increased glucose flux into the polyol pathway via aldose reductase (AR) is recognized as a major contributing factor for the pathogenesis of diabetic neuropathy, whereas little is known about the functional significance of AR in the peripheral nervous system. Spontaneously immortalized Schwann cell lines established from long-term cultures of AR-deficient and normal C57BL/6 mouse dorsal root ganglia and peripheral nerves can be useful tools for studying the physiological and pathological roles of AR. These cell lines, designated as immortalized knockout AR Schwann cells 1 (IKARS1) and 1970C3, respectively, demonstrated distinctive Schwann cell phenotypes, such as spindle-shaped morphology and immunoreactivity to S100, p75 neurotrophin receptor, and vimentin, and extracellular release of neurotrophic factors. Conditioned media obtained from these cells promoted neuronal survival and neurite outgrowth of cultured adult mouse dorsal root ganglia neurons. Microarray and real-time RT-PCR analyses revealed significantly down-regulated mRNA expression of polyol pathway-related enzymes, sorbitol dehydrogenase and ketohexokinase, in IKARS1 cells compared with those in 1970C3 cells. In contrast, significantly up-regulated mRNA expression of aldo-keto reductases (AKR1B7 and AKR1B8) and aldehyde dehydrogenases (ALDH1L2, ALDH5A1, and ALDH7A1) was detected in IKARS1 cells compared with 1970C3 cells. Exposure to reactive aldehydes (3-deoxyglucosone, methylglyoxal, and 4-hydroxynonenal) significantly up-regulated the mRNA expression of AKR1B7 and AKR1B8 in IKARS1 cells, but not in 1970C3 cells. Because no significant differences in viability between these two cell lines after exposure to these aldehydes were observed, it can be assumed that the aldehyde detoxification is taken over by AKR1B7 and AKR1B8 in the absence of AR.

Diabetic retinopathy has recently been defined as a highly specific neurovascular complication of diabetes. The chronic progression of the impairment of the interdependence of neurovascular units (NVUs) is associated with the pathogenesis of diabetic retinopathy. The NVUs consist of neurons, glial cells, and vascular cells, and the interdependent relationships between these cells are disturbed under diabetic conditions. Clinicians should understand and update the current knowledge of the neurovascular impairments in diabetic retinopathy. Above all, neuronal cell death is an irreversible change, and it is directly related to vision loss in patients with diabetic retinopathy. Thus, neuroprotective and vasoprotective therapies for diabetic retinopathy must be established. Understanding the physiological and pathological interdependence of the NVUs is helpful in establishing neuroprotective and vasoprotective therapies for diabetic retinopathy. This review focuses on the pathogenesis of the neurovascular impairments and introduces possible neurovascular protective therapies for diabetic retinopathy.

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.

Aldose reductase (AR) is an aldo-keto reductase that catalyzes the first step in the polyol pathway which converts glucose to sorbitol. Under normal glucose homeostasis the pathway represents a minor route of glucose metabolism that operates in parallel with glycolysis. However, during hyperglycemia the flux of glucose via the polyol pathway increases significantly, leading to excessive formation of sorbitol. The polyol pathway-driven accumulation of osmotically active sorbitol has been implicated in the development of secondary diabetic complications such as retinopathy, nephropathy, and neuropathy. Based on the notion that inhibition of AR could prevent these complications a range of AR inhibitors have been developed and tested; however, their clinical efficacy has been found to be marginal at best. Moreover, recent work has shown that AR participates in the detoxification of aldehydes that are derived from lipid peroxidation and their glutathione conjugates. Although in some contexts this antioxidant function of AR helps protect against tissue injury and dysfunction, the metabolic transformation of the glutathione conjugates of lipid peroxidation-derived aldehydes could also lead to the generation of reactive metabolites that can stimulate mitogenic or inflammatory signaling events. Thus, inhibition of AR could have both salutary and injurious outcomes. Nevertheless, accumulating evidence suggests that inhibition of AR could modify the effects of cardiovascular disease, asthma, neuropathy, sepsis, and cancer; therefore, additional work is required to selectively target AR inhibitors to specific disease states. Despite past challenges, we opine that a more gainful consideration of therapeutic modulation of AR activity awaits clearer identification of the specific role(s) of the AR enzyme in health and disease.

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., Highlights • The role of non-canonical activation of the Nrf2 signaling pathway in type II diabetes has not been determined. • Chronic activation of Nrf2 promotes a pro-diabetic shift in the liver polyol pathway that increases blood glucose levels. • Four newly identified Nrf2 target genes are responsible for the diabetogenic shift in liver carbohydrate metabolism.