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Diabetic retinopathy (DR) is a specific microvascular problem of diabetes, which is mainly caused by hyperglycemia and may lead to rapid vision loss. Dietary polyphenols have been reported to decrease the risk of DR. Apocynum venetum L. leaves are rich in polyphenolic compounds and are popular worldwide for their health benefits as a national tea drink. Building on previous findings of antioxidant activity and aldose reductase inhibition of A. venetum, this study investigated the chemical composition of polyphenol-rich extract of A. venetum leaves (AVL) and its protective mechanism on ARPE-19 cells in hyperglycemia. Ninety-three compounds were identified from AVL by LC-MS/MS, including sixty-eight flavonoids, twenty-one organic acids, and four coumarins. AVL regulated the polyol pathway by decreasing the expression of aldose reductase and the content of sorbitol, enhancing the Na+K+-ATPase activity, and weakening intracellular oxidative stress effectively; it also could regulate the expression of autophagy-related proteins via the AMPK/mTOR/ULK1 signaling pathway to maintain intracellular homeostasis. AVL could restore the polyol pathway, inhibit oxidative stress, and maintain intracellular autophagy to protect cellular morphology and improve DR. The study reveals the phytochemical composition and protective mechanisms of AVL against DR, which could be developed as a functional food and/or candidate pharmaceutical, aiming for retina protection in diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Diabetes is a multifunctional chronic disease that affects both the central and/or peripheral nervous systems. This study assessed whether nicotinamide (NAm) or conjugate of nicotinic acid with gamma-aminobutyric acid (N-GABA) could be potential neuroprotective agents against type 1 diabetes (T1D)-induced nervous system impairments in rats. After six weeks of T1D, induced by streptozotocin, nonlinear male Wistar rats were treated for two weeks with NAm (100 mg/kg, i. p.) or N-GABA (55 mg/kg, i. p.). Expression levels of myelin basic protein (MBP) were analyzed by immunoblotting. Polyol pathway parameters of the sciatic nerves were assessed spectrophotometrically, and their structure was examined histologically. NAm had no effect on blood glucose or body weight in T1D, while N-GABA reduced glucose by 1.5-fold. N-GABA also increased MBP expression by 1.48-fold, enhancing neuronal myelination, while NAm showed no such effect. Activation of the polyol pathway was observed in the T1D sciatic nerves. Both compounds decreased sorbitol content and aldose reductase activity, thereby alleviating changes similar to primary degeneration in the sciatic nerves and preventing peripheral neuropathy development. These results demonstrate that NAm and, more notably, N-GABA may exert neuroprotective effects against T1D-induced nervous system impairments by increasing MBP expression levels, improving myelination processes in the brain, inhibiting the polyol pathway, and partially restoring morphometric parameters in the sciatic nerves. This suggests their potential therapeutic efficacy as promising agents for the prevention of T1D-induced nervous system alterations. [ABSTRACT FROM AUTHOR]

Background: High glucose level and chronic inflammation are characteristic features of diabetic cutaneous wounds. Keratinocytes make up the epidermis and play an important role in skin repair. However, metabolomic changes of keratinocytes in chronic diabetic ulcers have not been fully studied. Methods and Results: This study used high levels of glucose combined with lipopolysaccharide to treat human HaCaT keratinocytes. Untargeted metabolomic combined with colorimetric assays were used to explore the changes of keratinocyte metabolites and related metabolic pathways caused by high glucose and lipopolysaccharide. Results demonstrated that high glucose combined with lipopolysaccharide treatment increased intracellular reactive oxygen species and impaired proliferation and migration of keratinocytes. Untargeted metabolomics analysis identified a total of 273 differential metabolites. Redox metabolism associated metabolites were largely altered. Reduced nicotinamide adenine dinucleotide, gamma-glutamylcysteine, superoxide dismutase activity and SOD2 gene expression were significantly upregulated while nicotinamide adenine dinucleotide, glutathione, glutathione peroxidase, several types of lysophosphatidylcholine, lysophosphatidylinositol, and GPR55 gene expression were downregulated. Alterations of glutathione and nicotinamide adenine dinucleotide were verified by colorimetric assays. For the first time, high glucose and LPS were observed to boost the levels of fructose, aldose reductase and sorbitol dehydrogenase of the polyol pathway in HaCaT cells. Further treatment of HaCaT with fructose leading to inhibition of cell proliferation and migration. Conclusions: Our data suggest high glucose combined with lipopolysaccharide significantly altered redox homeostasis associated metabolites and activate the polyol pathway in keratinocytes to impact cell proliferation and migration, providing new strategies for the treatment of chronic diabetic ulcers. [ABSTRACT FROM AUTHOR]

Cataracts are the world's leading cause of blindness, and diabetes is the second leading risk factor for cataracts after old age. Despite this, no preventative treatment exists for cataracts. The altered metabolism of excess glucose during hyperglycaemia is known to be the underlying cause of diabetic cataractogenesis, resulting in localised disruptions to fibre cell morphology and cell swelling in the outer cortex of the lens. In rat models of diabetic cataracts, this damage has been shown to result from osmotic stress and oxidative stress due to the accumulation of intracellular sorbitol, the depletion of NADPH which is used to regenerate glutathione, and the generation of fructose metabolites via the polyol pathway. However, differences in lens physiology and the metabolism of glucose in the lenses of different species have prevented the translation of successful treatments in animal models into effective treatments in humans. Here, we review the stresses that arise from hyperglycaemic glucose metabolism and link these to the regionally distinct metabolic and physiological adaptations in the lens that are vulnerable to these stressors, highlighting the evidence that chronic oxidative stress together with osmotic stress underlies the aetiology of human diabetic cortical cataracts. With this information, we also highlight fundamental gaps in the knowledge that could help to inform new avenues of research if effective anti-diabetic cataract therapies are to be developed in the future. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy (DN) is a neurodegenerative disorder that is primarily characterized by distal sensory loss, reduced mobility, and foot ulcers that may potentially lead to amputation. The multifaceted etiology of DN is linked to a range of inflammatory, vascular, metabolic, and other neurodegenerative factors. Chronic inflammation, endothelial dysfunction, and oxidative stress are the three basic biological changes that contribute to the development of DN. Although our understanding of the intricacies of DN has advanced significantly over the past decade, the distinctive mechanisms underlying the condition are still poorly understood, which may be the reason behind the lack of an effective treatment and cure for DN. The present study delivers a comprehensive understanding and highlights the potential role of the several pathways and molecular mechanisms underlying the etiopathogenesis of DN. Moreover, Schwann cells and satellite glial cells, as integral factors in the pathogenesis of DN, have been enlightened. This work will motivate allied research disciplines to gain a better understanding and analysis of the current state of the biomolecular mechanisms behind the pathogenesis of DN, which will be essential to effectively address every facet of DN, from prevention to treatment. [ABSTRACT FROM AUTHOR]

The polyol pathway is a primary mechanism for the formation of sorbitol, and its accumulation is a major factor in many diseases' complications. Importantly, there have previously been some indications that there is a relationship between polyol intermediates and thyroid hormones in hyperthyroidism state. Hence, this study aimed to shed light on the therapeutic impact of nano-quercetin (QT-NPs) on hyperthyroidism via inhibiting the polyol pathway. Besides control groups, hyperthyroidism was triggered in the rats by 100 μg/kg of l-thyroxin and further treated with quercetin (QT) and nano-quercetin (10 mg/kg body weight). Additionally, levels of thyroid hormones (T3 and T4), oxidative markers, and the antioxidant system were monitored. Besides histological investigation of thyroid gland, the level of aldose reductase was estimated by qPCR. The obtained findings indicated an elevation of T3 and T4 which indicated hyperthyroidism. This hyperthyroid state was accompanied by an elevation in oxidative stress and a decline in antioxidant status. Importantly, the expression level of aldose reductase was elevated, as was the level of sorbitol. The treatment with QT and QT-NPs potentially reduced the expression level of aldose reductase and the concentration of sorbitol, indicating the inhibition capability of QT and QT-NPs on the polyol pathway key enzyme. Furthermore, rat groups treated with QT and QT-NPs showed an elevation in the antioxidant system (GSH, GPx) with a notable decline in the oxidative stress marker MDA. Furthermore, histopathological examination of the thyroid tissue of hyperthyroidism group treated with QT-NPs confirms the potential effect of QT-NPs on the thyroid tissue. In conclusion, QT-NPs showed therapeutic superiority over QT in hyperthyroidism treatment through inhibition of aldose reductase, which is the key enzyme in the polyol pathway. [ABSTRACT FROM AUTHOR]

The escalating global prevalence of diabetes mellitus (DM) over the past two decades has led to a persistent high incidence of diabetic retinopathy (DR), necessitating screening for early symptoms and proper treatment. Effective management of DR aims to decrease vision impairment by controlling modifiable risk factors including hypertension, obesity, and dyslipidemia. Moreover, systemic medications and plant-based therapy show promise in advancing DR treatment. One of the key mechanisms related to DR pathogenesis is the polyol pathway, through which aldose reductase (AR) catalyzes the conversion of glucose to sorbitol within various tissues, including the retina, lens, ciliary body and iris. Elevated glucose levels activate AR, leading to osmotic stress, advanced glycation end-product formation, and oxidative damage. This further implies chronic inflammation, vascular permeability, and angiogenesis. Our comprehensive narrative review describes the therapeutic potential of aldose reductase inhibitors in treating DR, where both synthetic and natural inhibitors have been studied in recent decades. Our synthesis aims to guide future research and clinical interventions in DR management. [ABSTRACT FROM AUTHOR]

NAD synthetase 1 (encoded by the gene NADSYN1) is a cytosolic enzyme that catalyzes the final step in the biosynthesis of nicotinamide adenine dinucleotide (NAD+) from tryptophan and nicotinic acid. NADSYN1 deficiency has recently been added to the spectrum of congenital NAD+ deficiency disorders. To gain insight into the metabolic consequences of NADSYN1 deficiency, the encoding gene was disrupted in A549 and HEK293T cells, and the metabolome was profiled in the presence of different NAD+ precursors, including tryptophan, nicotinamide and nicotinic acid. We demonstrate that when precursors of the NAD+ salvage pathway in the form of nicotinamide become limiting, NADSYN1 deficiency results in a decline in intracellular NAD+ levels even in the presence of other potential NAD+ sources such as tryptophan and nicotinic acid. As a consequence, alterations in 122 and 69 metabolites are observed in NADSYN1-deficient A549 and HEK293T cells compared to the wild-type cell line (FC > 2 and p < 0.05). We thus show that NADSYN1 deficiency results in a metabolic phenotype characterized by alterations in glycolysis, the TCA cycle, the pentose phosphate pathway, and the polyol pathway. [ABSTRACT FROM AUTHOR]

Increased adiposity of both visceral and perivascular adipose tissue (PVAT) depots is associated with an increased risk of diabetes and cardiovascular disease (CVD). Under healthy conditions, PVAT modulates vascular tone via the release of PVAT-derived relaxing factors, including adiponectin and leptin. However, when PVAT expands with high-fat diet (HFD) feeding, it appears to contribute to the development of endothelial dysfunction (ED). Yet, the mechanisms by which PVAT alters vascular health are unclear. Aldose reductase (AR) catalyzes glucose reduction in the first step of the polyol pathway and has been long implicated in diabetic complications including neuropathy, retinopathy, nephropathy, and vascular diseases. To better understand the roles of both PVAT and AR in HFD-induced ED, we studied structural and functional changes in aortic PVAT induced by short-term HFD (60% kcal fat) feeding in wild type (WT) and aldose reductase-null (AR-null) mice. Although 4 weeks of HFD feeding significantly increased body fat and PVAT mass in both WT and AR-null mice, HFD feeding induced ED in the aortas of WT mice but not of AR-null mice. Moreover, HFD feeding augmented endothelial-dependent relaxation in aortas with intact PVAT only in WT and not in AR-null mice. These data indicate that AR mediates ED associated with short-term HFD feeding and that ED appears to provoke 'compensatory changes' in PVAT induced by HFD. As these data support that the ED of HFD feeding is AR-dependent, vascular-localized AR remains a potential target of temporally selective intervention. [ABSTRACT FROM AUTHOR]

Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is one of the leading causes of death among patients diagnosed with diabetes mellitus. Despite the growing knowledge about the pathogenesis of DKD, we still do not have effective direct pharmacotherapy. Accurate blood sugar control is essential in slowing down DKD. It seems that metformin has a positive impact on kidneys and this effect is not only mediated by its hypoglycemic action, but also by direct molecular regulation of pathways involved in DKD. The molecular mechanism of DKD is complex and we can distinguish polyol, hexosamine, PKC, and AGE pathways which play key roles in the development and progression of this disease. Each of these pathways is overactivated in a hyperglycemic environment and it seems that most of them may be regulated by metformin. In this article, we summarize the knowledge about DKD pathogenesis and the potential mechanism of the nephroprotective effect of metformin. Additionally, we describe the impact of metformin on glomerular endothelial cells and podocytes, which are harmed in DKD. [ABSTRACT FROM AUTHOR]

Background: Saliva plays essential roles in different biological processes. Autonomic receptors stimulation is the main regulator of its secretion. Ca2+ acts as a 2nd messenger via increasing its cytoplasmic-level (i-Ca2+) &decreasing its endoplasmic reticulum-level (ER-Ca2+) with subsequent protein synthesis as a-amylase and water flow through aquaporin-5 channels (AQP-5). Sarco-ER Ca2+-ATPase (SERCA) pumps i-Ca2+ back to ER-Ca2+ maintaining low i-Ca2+ during rest and allowing its increase during salivary activation. Polyol-pathway overactivity with biological molecules glycation and oxidative-stress is the main mechanism of diabetic complications as xerostomia. As aldose-reductase (AR) is its key-enzyme, multiple ARinhibitors (ARIs) were newly explored to cure diabetic complications. Aim of work: Investigating SERCA &AQP-5 roles in diabetes-induced xerostomia molecular mechanism in adult male albino rats &the potential ARIs therapeutic effect. Materials &Methods: 32 rats were divided into 2 groups: control &experimental [received 55mg/kg streptozotocin to induce diabetes]. 18 hyperglycemic rats were divided into 3 subgroups: diabetic, diabetic/recovery &diabetic/ARIs [received daily oral 57 mg/kg Epalrestat for 4 weeks]. Serum glucose measurement, saliva collection &biochemical, histological, immunohistochemical [for active SERCA, AQP-5, inactive SERCA &caspase-3] and morphometric studies were done. Results: All serological, biochemical &histological manifestations of diabetes &xerostomia deteriorated from diabetic subgroup to diabetic/recovery subgroup. However, Epalrestat use evidently improved xerostomia manifestations but not diabetic manifestations. Conclusion: The main molecular mechanism of diabetesinduced xerostomia is polyol-pathway overactivity and consequent SERCA inactivation, i-Ca2+ overload, ER-stress, AQP-5 reduction, &a-amylase improper folding. Epalrestat, an ARI, ameliorates such xerostomia by blocking this pathway and preventing these changes with no effect on diabetes itself. [ABSTRACT FROM AUTHOR]

There is increasing evidence that either ingested or produced fructose may have a role in metabolic syndrome. While not commonly considered a criterion for metabolic syndrome, cardiac hypertrophy is often associated with metabolic syndrome, and its presence carries increased cardiovascular risk. Recently it has been shown that fructose and fructokinase C (KHK) can be induced in cardiac tissue. Here we tested whether diet-induced metabolic syndrome causes heart disease associated with increased fructose content and metabolism and whether it can be prevented with a fructokinase inhibitor (osthole). Male Wistar rats were provided a control diet (C) or high fat/sugar diet for 30 days (MS), with half of the latter group receiving osthol (MS+OT, 40 mg/kg/d). The Western diet increased fructose, uric acid, and triglyceride concentrations in cardiac tissue associated with cardiac hypertrophy, local hypoxia, oxidative stress, and increased activity and expression of KHK in cardiac tissue. Osthole reversed these effects. We conclude that the cardiac changes in metabolic syndrome involve increased fructose content and its metabolism and that blocking fructokinase can provide cardiac benefit through the inhibition of KHK with modulation of hypoxia, oxidative stress, hypertrophy, and fibrosis. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is a tissue-specific neurovascular impairment of the retina in patients with both type 1 and type 2 diabetes. Several pathological factors are involved in the progressive impairment of the interdependence between cells that consist of the neurovascular units (NVUs). The advanced glycation end-products (AGEs) are one of the major pathological factors that cause the impairments of neurovascular coupling in diabetic retinopathy. Although the exact mechanisms for the toxicities of the AGEs in diabetic retinopathy have not been definitively determined, the AGE-receptor of the AGE (RAGE) axis, production of reactive oxygen species, inflammatory reactions, and the activation of the cell death pathways are associated with the impairment of the NVUs in diabetic retinopathy. More specifically, neuronal cell death is an irreversible change that is directly associated with vision reduction in diabetic patients. Thus, neuroprotective therapies must be established for diabetic retinopathy. The AGEs are one of the therapeutic targets to examine to ameliorate the pathological changes in the NVUs in diabetic retinopathy. This review focuses on the basic and pathological findings of AGE-induced neurovascular abnormalities and the potential therapeutic approaches, including the use of anti-glycated drugs to protect the AGE-induced impairments of the NVUs in diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Background: This work elucidates the first cellular and molecular causes of cataractogenesis. Current paradigm presupposes elevated blood glucose as a prerequisite in diabetic cataractogenesis. Novel evidence in our model of diabetic cataract challenges this notion and introduces immune cell migration to the lens and epithelial-mesenchymal transformation (EMT) of lens epithelial cells (LECs) as underlying causes. Methods: Paucity of suitable animal models has hampered mechanistic studies of diabetic cataract, as most studies were traditionally carried out in acutely induced hyperglycemic animals. We introduced diabetic cataract in the Nile grass rat (NGR) that spontaneously develops type 2 diabetes (T2D) and showed its closeness to the human condition. Specialized stereo microscopy with dual bright-field illumination revealed novel hyperreflective dot-like microlesions in the inner cortical regions of the lens. To study immune cell migration to the lens, we developed a unique in situ microscopy technique of the inner eye globe in combination with immunohistochemistry. Results: Contrary to the existing paradigm, in about half of the animals, the newly introduced hyper reflective dot-like microlesions preceded hyperglycemia. Even though the animals were normoglycemic, we found significant changes in their oral glucose tolerance test (OGTT), indicative of the prediabetic stage. The microlesions were accompanied with significant immune cell migration from the ciliary bodies to the lens, as revealed in our novel in situ microscopy technique. Immune cells adhered to the lens surface, some traversed the lens capsule, and colocalized with apoptotic nuclei of the lens epithelial cells (LECs). Extracellular degradations, amorphous material accumulations, and changes in E-cadherin expressions showed epithelial-mesenchymal transformation (EMT) in LECs. Subsequently, lens fiber disintegration and cataract progression extended into cortical, posterior, and anterior subcapsular cataracts. Conclusions: Our results establish a novel role for immune cells in LEC transformation and death. The fact that cataract formation precedes hyperglycemia challenges the prevailing paradigm that glucose initiates or is necessary for initiation of the pathogenesis. Novel evidence shows that molecular and cellular complications of diabetes start during the prediabetic state. These results have foreseeable ramifications for early diagnosis, prevention and development of new treatment strategies in patients with diabetes. [ABSTRACT FROM AUTHOR]

Diabetes foot ulcer (DFU) affects around one-third of diabetic patients, which are mostly caused by peripheral neurovascular disease or peripheral neuropathy. Since diabetic foot ulcers are persistent and difficult to cure, the present study contains a literature review for a better understanding of the neuropathic and ischemic characteristics of diabetes, their control, prevention, and treatment. The researchers discovered that the inhibitors of sorbitol dehydrogenase, AR, Protein Kinase C (PKC) activation, activators of myo-inositol bisphosphatase, nitric oxide synthase and many other enzymes were found to play salient roles in the polyol pathway of diabetic neuropathy. It can be concluded that key elements of the polyol pathway play a vital role in the control, prevention, management, and treatment of diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

Aldose reductase (AR, AKR1B1; EC 1.1.1.21) is an aldo‐keto reductase that has been widely investigated as an enzyme crucially involved in the pathogenesis of several chronic complications, including nephropathy, neuropathy, retinopathy, and cataracts associated with diabetes mellitus. Although sulfonamides have been reported to possess many other biological activities, in continuation of our interest in designing and discovering potent inhibitors of AR, herein, we have evaluated the AR inhibitory potential of N‐substituted phthalazine sulfonamide derivatives 5a‐l. The biological studies revealed that all the derivatives show excellent activity against AR, with KI constants ranging from 67.73 to 495.20 nM. Among these agents, 4‐(6‐nitro‐1,4‐dioxo‐1,2,3,4‐tetrahydrophthalazine‐2‐carbonyl)benzenesulfonamide (5e) and 1,4‐dioxo‐3‐(4‐sulfamoylbenzoyl)‐1,2,3,4‐tetrahydrophthalazine‐6‐carboxylic acid (5f) showed prominent inhibitory activity with KI values of 67.73 and 148.20 nM, respectively, vs AR and were found to be more potent than epalrestat (KI = 852.50 nM), the only AR inhibitor currently used in the therapy. Moreover, molecular docking studies were also performed to rationalize binding site interactions of these sulfonamides (5a‐l) with the target enzyme AR. According to ADME‐Tox, predicts were also determined that these derivatives be ARIs displaying suitable drug‐like properties. The sulfonamides identified in this study may be used to develop lead therapeutic agents inhibiting diabetic complications. [ABSTRACT FROM AUTHOR]

Background: Hyperglycaemia is known to result in oxidative stress tissue injury and dysfunction. Interestingly, studies have reported hepatic and renal oxidative stress injury during prediabetes; however, any injury to the myocardium during prediabetes has not been investigated. Hence this study aims to assess changes in the myocardial tissue in an HFHC diet-induced model of prediabetes.Methods: Male Sprague Dawley rats were randomly grouped into non-prediabetes and prediabetes (n = 6 in each group) and consumed a standard rat chow or fed a high-fat-high-carbohydrate diet respectively for a 20-week prediabetes induction period. Post induction, prediabetes was confirmed using the ADA criteria. Aldose reductase, NADH oxidase 1, superoxide dismutase, glutathione peroxide, cardiac troponins were analysed in cardiac tissue homogenate using specific ELISA kits. Lipid peroxidation was estimated by determining the concentration of malondialdehyde in the heart tissue homogenate according to the previously described protocol. Myocardial tissue sections were stained with H&E stain and analysed using Leica microsystem. All data were expressed as means ± SEM. Statistical comparisons were performed with Graph Pad instat Software using the Student's two-sided t-test. Pearson correlation coefficient was calculated to assess the association. Value of p < 0.05 was considered statistically significant.Results: The prediabetes group showed a markedly high oxidative stress as indicated by significantly increased NADH oxidase 1 and malondialdehyde while superoxide dismutase and glutathione peroxide were decreased compared to non-prediabetes group. There was no statistical difference between cardiac troponin I and T in the non-prediabetes and prediabetes groups. Cardiac troponins had a weak positive association with glycated haemoglobin.Conclusion: The findings of this study demonstrate that prediabetes is associated with myocardial injury through oxidative stress. Future studies are to investigate cardiac contractile function and include more cardiac biomarkers. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: During hyperglycaemia, some glucose bypasses glycolysis and is metabolised via the potentially neurotoxic polyol pathway, in which glucose is metabolised to sorbitol and fructose. Increased polyol concentrations have been demonstrated in the cerebrospinal fluid (CSF) of neurological patients with and without diabetes mellitus. However, polyol levels in patients without evident neurological abnormalities have not been investigated so far. The aim of this study was to determine CSF polyol concentrations in patients without major neurological disease with normal or elevated CSF glucose concentrations. Methods: This observational cohort study used CSF and plasma analyses, as well as clinical data, from 30 participants of the Anaesthetic Biobank of Cerebrospinal Fluid study. Biomaterial was collected from adult patients scheduled for elective surgery under spinal anaesthesia. CSF polyol concentrations were measured by GC/flame ionisation detector in ten patients with normal CSF glucose levels (group 1), ten patients with elevated CSF glucose levels (group 2) and ten patients with elevated CSF glucose levels and type 2 diabetes (group 3). We compared the concentrations of plasma glucose, CSF glucose, sorbitol and fructose, and CSF polyol/glucose ratios between the three groups, and determined the correlation between plasma glucose levels and CSF glucose, sorbitol and fructose levels. Results: Groups 2 and 3 had significantly higher CSF fructose levels compared with group 1 (p=0.036 and p<0.001, respectively). Group 3 showed significant differences compared with groups 1 and 2 for CSF sorbitol (p<0.001 and 0.036, respectively). Moreover, patients with diabetes had a significantly higher CSF sorbitol/glucose ratio compared with patients without diabetes. There was a strong positive correlation between plasma glucose and CSF glucose, sorbitol and fructose. Finally, age, sex, CSF/plasma albumin ratio and preoperative cognitive function scores were significantly correlated with plasma glucose and CSF glucose, sorbitol and fructose levels. Conclusions/interpretation: Hyperglycaemia causes a proportional increase in polyol concentrations in CSF of patients without major neurological disease. Furthermore, this study provides the first indication of upregulation of the cerebral polyol pathway in patients with diabetes without evident neurological abnormalities. [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. [ABSTRACT FROM AUTHOR]

Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of drugs for the treatment of type 2 diabetes mellitus (T2DM), which have cardio-renal protective activity. Some studies have also found that this drug may have an eye-protective effect, especially in preventing diabetic retinopathy (DR). A search was conducted on PubMed and Google Scholar for all articles published from January 2007 to May 2022. This paper provides a new insight into how new emerging diabetic therapy may be beneficial in the case of DR. SGLT2 inhibitors have been proven to delay DR progression. However, the drug mechanism in the pathophysiology of diabetic retinopathy has not yet been established. In clinical practice, using SGLT2 inhibitors is beneficial as it offers multiple advantages. They can control blood sugar levels while simultaneously suppressing the progression of DR and DME. There is potential that the use of other expensive and prolonged therapeutic modalities may no longer be necessary, reducing the burden of treatment for patients. [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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Propofol, a widely used short‐acting intravenous sedative agent, has gradually gained attention due to the tumour‐suppressing role and non‐anaesthetic effect. Dysfunction of metabolic reprogramming has been recognised as a well‐documented factor for tumour progression. The aim of this study is to explore the effect of propofol on the polyol pathway in gastric cancer cells. In this study, we found that propofol treatment led to a significant downregulation of cell proliferation in BGC823 and GES‐1 cells, which was attributed to the decreased AR‐mediated polyol pathway. Both aldo‐keto reductase family 1, member B1 (AKR1B1) and AKR1B10 were significantly reduced in BGC823 and GES‐1 cells in response to propofol stimulation, leading to decreased AR activity and sorbitol level. Addition of sorbitol could reverse the inhibitory effect of propofol on cell proliferation. Mechanically, propofol treatment drastically inhibited phosphorylation and nuclear translocation of nuclear factor (erythroid‐derived 2)‐like 2 (NRF2), subsequently decreased the binding of NRF2 to AR promoter. Overexpression of NRF2 resulted in the recovery of AR expression in gastric cancer cell with propofol treatment. Taken together, these finding showed that propofol suppressed cell proliferation in BGC823 and GES‐1 cell through NRF2‐mediated polyol pathway, which would aid the selection of sedation for patients with gastric cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

One of the processes involved in pathogenesis of diabetic complications is the polyol pathway, which is catalyzed by the enzymes – aldose reductase and sorbitol dehydrogenase. Inhibition of one, or both, of these enzymes will shut down the polyol pathway ameliorating diabetic complications. Consumption of leafy vegetables is a dietary regime for management of diabetes mellitus and its complications. Inhibitory effects of leafy vegetables on activities of the polyol pathway enzymes aldose reductase and sorbitol dehydrogenase, and mode(s) of inhibition of these enzymes by the most effective plant were evaluated. Aqueous extract of leaves of African eggplant (Solanum macrocarpon L), bitter leaf (Vernonia amygdalina Del.), fluted pumpkin (Telfairia occidentalis Hook.) and clove basil leaf (Ocimum gratissimum L), were incubated with substrates (glucose and sorbitol) and enzymes, and their percent inhibition of enzymes determined spectrophotometrically. Due to low IC50 value, the aqueous extract of bitter leaf was used to assess kinetics of both enzymes. With exception of African eggplant, all plants displayed stronger inhibition of sorbitol dehydrogenase than aldose reductase. Vernonia amygdalina exhibited the lowest IC50 for aldose reductase (78.03 µg∙mL−1) and sorbitol dehydrogenase (22.17 µg∙mL−1). Vernonia amygdalina inhibited aldose reductase and sorbitol dehydrogenase in a noncompetitive, and mixed non-competitive manner, respectively. The V. amygdalina extract displayed potent inhibition of polyol pathway enzymes, and it needs to be determined if consumption affects the responses. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]

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]

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]

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]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Purpose: Lutein's role on chronic hyperglycemia-induced oxidative stress and associated glucose homeostasis in heart and kidney is limited. Purpose of the study is to investigate the effect of lutein on cardiac and renal polyol pathway enzymes and oxidative stress markers under hyperglycemia-induced oxidative stress condition using streptozotocin (STZ)-injected rat model. Methods: STZ-induced hyperglycemic (fasting blood glucose ≥11 mM) male Wistar rats were divided into two groups ( n = 11/group). Group 1 received micellar lutein (39 nmol/day/rat) and group 2 (negative control) received micelle without lutein for 8 weeks. A separate group (no STZ injected) served as a positive control ( n = 11/group). Oral glucose tolerance test (OGTT), biweekly urine glucose and activities of aldose reductase (AR) and sorbitol dehydrogenase (SDH) enzymes were assessed. Activities of antioxidant enzymes and antioxidant level were also evaluated. Results: Lutein-administered hyperglycemic rats showed better glucose tolerance as evidenced with OGTT and biweekly urine glucose when compared to negative control. Activities of AR and SDH were decreased in heart and kidney of lutein-fed hyperglycemic rats. Also, they had significantly ( p < 0.05) decreased malondialdehyde levels (66, 34, and 33 %) and increased reduced glutathione level (81, 18 and 92 %) in serum, heart and kidney, respectively. Altered antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase were also affected in serum, heart and kidney of lutein-fed diabetic group. Conclusion: Lutein prevented cardiac and renal injury in STZ-induced hyperglycemic rats due to potential amelioration of altered activities in polyol pathway and oxidative stress markers. [ABSTRACT FROM AUTHOR]

Cataract is one of the primitive secondary complications of diabetes mellitus and contributes to 50% blindness worldwide. Aldose reductase (AR) is the first and rate limiting enzyme in the intracellular polyol pathway responsible for the development of cataract. Thus, there is an imperative need for modest, non-surgical way in order to treat cataract. In Ayurveda, Punica granatum (Pomegranate) is considered as 'a pharmacy unto itself'. Pomegranate leaves are traditionally used for their anti-diabetic activity. In this study, we investigated AR inhibitory activity and anti-cataract potential of Pomegranate leaves in glucose - induced cataract in goat lens. AR inhibitory activity was evaluated in vitro in goat lenses. In glucose induced cataract model, goat lenses were incubated in artificial aqueous humor containing 55 mM glucose along with methanolic extract of Punica granatum leaves (MPGL) or quercetin for 72 h. After 72 h, photographic evaluation of the lens was carried out and the lens antioxidant parameters were determined. Different concentrations of MPGL were found to inhibit lens AR activity with an IC50 value of 83.55 ± 3.92 μg/ml. Quercetin was taken as positive control which exhibited 56.461% AR inhibition at a concentration of 500 μg/ml. Cataractous lenses exhibited marked opacity and decrease in the levels of reduced glutathione and superoxide dismutase. Treatment with MPGL and quercetin prevented the opacity and restored back the antioxidant activity. Together, Punica granatum leaves ameliorated glucose-induced cataractogenesis via AR inhibition, reduction in oxidative stress and improvement in antioxidant defense system. [ABSTRACT FROM AUTHOR]

Erythritol is the preferential carbon source for most brucellae, a group of facultative intracellular bacteria that cause a worldwide zoonosis. Since this polyol is abundant in genital organs of ruminants and swine, it is widely accepted that erythritol accounts at least in part for the characteristic genital tropism of brucellae. Nevertheless, proof of erythritol availability and essentiality during Brucella intracellular multiplication has remained elusive. To investigate this relationship, we compared ΔeryH (erythritolsensitive and thus predicted to be attenuated if erythritol is present), 1eryA (erythritoltolerant but showing reduced growth if erythritol is a crucial nutrient) and wild type B. abortus in various infection models. This reporting system indicated that erythritol was available but not required for B. abortus multiplication in bovine trophoblasts. However, mice and humans have been considered to lack erythritol, and we found that it was available but not required for B. abortus multiplication in human and murine trophoblastic and macrophage-like cells, and in mouse spleen and conceptus (fetus, placenta and envelopes). Using this animal model, we found that B. abortus infected cells and tissues contained aldose reductase, an enzyme that can account for the production of erythritol from pentose cycle precursors. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: The anti-glycative and anti-oxidative effects from Houttuynia cordata leaves aqueous extract (HCAE) in heart and kidney of diabetic mice were examined. Methods: HCAE, at 1 or 2 %, was supplied in drinking water for 8 weeks. Plasma glucose and blood urea nitrogen (BUN) levels and creatine phosphokinase (CPK) activity were measured. The production of oxidative and inflammatory factors was determined. Activity and protein expression of associated enzymes or regulators were analyzed. Results: HCAE intake at both doses lowered plasma glucose and BUN levels, and CPK activity and also restored creatinine clearance rate in diabetic mice. HCAE intake, only at 2 %, retained plasma insulin levels ( P < 0.05). HCAE reduced reactive oxygen species, protein carbonyl, interleukin-6, tumor necrosis factor-alpha, N-(carboxymethyl)-lysine, pentosidine and fructose levels, and reserved glutathione content in heart and kidney of diabetic mice ( P < 0.05). Diabetes enhanced aldose reductase (AR) activity and protein expression in heart and kidney ( P < 0.05). HCAE intake at both doses decreased renal AR activity and protein expression, but only at 2 % lowered cardiac AR activity and protein expression ( P < 0.05). Diabetes increased protein expression of RAGE, p47 and gp91, nuclear factor kappa-B (NF-κB) p50, NF-κB p65 and mitogen-activated protein kinase in heart and kidney ( P < 0.05). HCAE intake only at 2 % limited RAGE expression, but at 1 and 2 % downregulated p47, NF-κB p65 and p-p38 expression in these organs ( P < 0.05). Conclusions: These findings suggest that Houttuynia cordata leaves aqueous extract could ameliorate cardiac and renal injury under diabetic condition. [ABSTRACT FROM AUTHOR]

The incidence of cardiovascular complications associated with hyperglycemia is a growing global health problem. This review discusses the link between hyperglycemia and cardiovascular diseases onset, focusing on the role of recently emerging downstream mediators, namely, oxidative stress and glucose metabolic pathway perturbations. The role of hyperglycemia-mediated activation of nonoxidative glucose pathways (NOGPs) [i.e., the polyol pathway, hexosamine biosynthetic pathway, advanced glycation end products (AGEs), and protein kinase C] in this process is extensively reviewed. The proposal is made that there is a unique interplay between NOGPs and a downstream convergence of detrimental effects that especially affect cardiac endothelial cells, thereby contributing to contractile dysfunction. In this process the AGE pathway emerges as a crucial mediator of hyperglycemia-mediated detrimental effects. In addition, a vicious metabolic cycle is established whereby hyperglycemia-induced NOGPs further fuel their own activation by generating even more oxidative stress, thereby exacerbating damaging effects on cardiac function. Thus NOGP inhibition, and particularly that of the AGE pathway, emerges as a novel therapeutic intervention for the treatment of cardiovascular complications such as acute myocardial infarction in the presence hyperglycemia. [ABSTRACT FROM AUTHOR]

Background: The Zolfino bean is avariety 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. [ABSTRACT FROM AUTHOR]

Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury. [ABSTRACT FROM AUTHOR]

Prevention of hyperglycemia and enhancement of antioxidant defense mechanisms remain major goals in the treatment of diabetic cataract. Earlier, we reported strong anti-hyperglycemic and in vitro antioxidant potential of the combined formulation of grape seed extract and Zincovit tablets. Therefore, the current study was designed to investigate effects of combined formulation of grape seed extract and Zincovit tablets against streptozocin-induced diabetic cataract in Wistar rats. Adult Wistar rats were selected and diabetes was induced by streptozocin (35 mg/kg, i.p) and divided into four groups (group II-V). The normal control (group I) and streptozocin-induced diabetic cataract control rats received only vehicle. Groups III, IV and V animals received orally 40, 80 and 160 mg/kg of combined formulation of Zincovit tablets with grape seed extract respectively for a period of 150 days. The biochemical pathways involved in the pathogenesis of cataract such as oxidative stress, polyol pathway and alterations in adenosine triphosphate, glucose-6-phosphate dehydrogenase and blood glucose were investigated, to understand the possible mechanism of action of combined formulation of grape seed extract and Zincovit tablets. Rats treated with combined formulation of grape seed extract and Zincovit tablets delayed the progression of diabetic cataract as well as it showed significant alterations in oxidative stress markers along with blood glucose, aldose reductase, glucose-6-phosphate dehydrogenase and adenosine triphosphate level in lens. Over all, the results suggest that single combined formulation of grape seed extract and Zincovit tablets may be of great value in delaying diabetic cataract of human subjects as nutritional food supplement. [ABSTRACT FROM AUTHOR]

The ability of flavonoids to affect multiple key pathways of glucose toxicity, as well as to attenuate inflammation has been well documented. In this study, the inhibition of rat lens aldose reductase by 3,7-di-hydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxy-phenyl]-5-hydroxy-chromen-4-one (compound 1), was studied in greater detail in comparison with the parent quercetin (compound 2). The inhibition activity of 1, characterized by IC50 in low micromolar range, surpassed that of 2. Selectivity in relation to the closely related rat kidney aldehyde reductase was evaluated. At organ level in isolated rat lenses incubated in the presence of high glucose, compound 1 significantly inhibited accumulation of sorbitol in a concentration-dependent manner, which indicated that 1 was readily taken up by the eye lens cells and interfered with cytosolic aldose reductase. In addition, compound 1 provided macroscopic protection of colonic mucosa in experimental colitis in rats. At pharmacologically active concentrations, compound 1 and one of its potential metabolite 2-chloro-3-hydroxy-[1,4]-naphthoquinone (compound 3) did not affect osmotic fragility of red blood cells. [ABSTRACT FROM AUTHOR]