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Spinal cord contusion injury results in Wallerian degeneration of spinal cord axonal tracts, which are necessary for locomotor function. Axonal swelling and loss of axonal density at the contusion site, characteristic of Wallerian degeneration, commence within hours of injury. Tempol, a superoxide dismutase mimetic, was previously shown to reduce the loss of spinal cord white matter and improve locomotor function in an experimental model of spinal cord contusion, suggesting that tempol treatment might inhibit Wallerian degeneration of spinal cord axons. Here, we report that tempol partially inhibits Wallerian degeneration, resulting in improved locomotor recovery. We previously reported that Wallerian degeneration is reduced by inhibitors of aldose reductase (AR), which converts glucose to sorbitol in the polyol pathway. We observed that tempol inhibited sorbitol production in the injured spinal cord to the same extent as the AR inhibitor, sorbinil. Tempol also prevented post-contusion upregulation of AR (AKR1B10) protein expression within degenerating axons, as previously observed for AR inhibitors. Additionally, we hypothesized that tempol inhibits axonal degeneration by preventing loss of the glutathione pool due to polyol pathway activity. Consistent with our hypothesis, tempol treatment resulted in greater glutathione content in the injured spinal cord, which was correlated with increased expression and activity of gamma glutamyl cysteine ligase (γGCL; EC 6.3.2.2), the rate-limiting enzyme for glutathione synthesis. Administration of the γGCL inhibitor buthionine sulfoximine abolished all observed effects of tempol administration. Together, these results support a pathological role for polyol pathway activation in glutathione depletion, resulting in Wallerian degeneration after spinal cord injury (SCI). Interestingly, methylprednisolone, oxandrolone, and clenbuterol, which are known to spare axonal tracts after SCI, were equally effective in inhibiting polyol pathway activation. These results suggest that prevention of AR activation is a common target of many disparate post-SCI interventions. [ABSTRACT FROM AUTHOR]

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]

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]

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.

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.

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]

The survival, motility and capacitation of sperm in the female reproductive tract are important prerequisites for fertilization. The uterus is the main location for sperm capacitation. One of the most important physiological functions of the endometrial epithelium is to create a suitable uterine environment under the regulation of ovarian hormones, to ensure sperm capacitation. The composition of uterine fluid directly affects sperm capacitation. Fructose is an important component of semen that supports sperm viability and motility. Aldose reductase, a rate-limiting enzyme in the polyol pathway, metabolizes sorbitol and fructose, thereby supplying cells with necessary energy for functional activities. Existing studies have reported the presence aldose reductase in the endometrium, leading us to hypothesize that its expression in endometrial epithelium might promote sperm capacitation by maintaining the uterine environment. Yet, the mechanism of regulation has not been clarified. In this study, we investigated the expression of aldose reductase in mouse endometrial epithelium and its potential role in sperm capacitation. We initially investigated the periodic characteristics of glucose, fructose and sorbitol in uterine fluid. We then studied the temporal and spatial characteristics of aldose reductase in the endometrial epithelium. Next, we examined the effect of aldose reductase on glucose, fructose and sorbitol in uterine fluid. Finally, we explored the effect of aldose reductase on sperm capacitation and fertilization. The results showed that glucose and fructose content in uterine fluid and the expression of aldose reductase fluctuated periodically during physiological periods. Inhibition of aldose reductase in the endometrial epithelium interfered with sperm capacitation and fertilization by reducing the fructose levels in the uterine fluid. To conclude, the aldose reductase-mediated polyol pathway in endometrial epithelial cells is essential to maintain an appropriate fructose environment in the uterine fluid for sperm capacitation and fertilization. [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.

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]

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

Abstract 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.

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.

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]

Abstract 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

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: Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF).Methods: Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers.Results: The ARISE-HF Trial is fully enrolled.Conclusions: This report describes the rationale and study design of ARISE-HF. [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]

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.

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]

• Quantification of total polyphenols by HPLC. • Inhibition of aldose reductase activity by rosmarinic acid. • Μolecular docking analysis of rosmarinic acid with aldose reductase. Many complications of diabetes have been associated with the accumulation of intracellular sorbitol caused by excessive activity of aldose reductase (ALR2). ALR2 is a member of the aldo-keto reductases (AKR) superfamily and has gained significant attention due to its role in the development of diabetic complications. Inhibiting ALR2 could help prevent or delay some of these problems. Coleus forskohlii is a natural medicinal plant that is known for its medicinal effects and is also used as a beverage in several European countries. High-performance liquid chromatography (HPLC) was used to measure the polyphenol content of aqueous leaf extracts of C. forskohlii, and it was found that rosmarinic acid (RA) had the highest concentration (1.25 mg/g) compared to other polyphenols. In vitro bioassays were conducted to evaluate the inhibitory effect of RA on ALR2. RA significantly and dose-dependently reduced the build-up of sorbitol in human erythrocytes under high glucose conditions. Molecular docking studies suggest that RA, which is an essential polyphenol, could be a potential ALR2 inhibitor. This study is the first to show that RA has an IC50 value of 56 % to exhibit an inhibitory effect against ALR2. [Display omitted] [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.

Background: Hepatic insulin signaling suppresses gluconeogenesis but promotes de novo lipid synthesis. Paradoxically, hepatic insulin resistance (HIR) enhances both gluconeogenesis and de novo lipid synthesis. Elucidation of the etiology of this paradox, which participates in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, the metabolic syndrome and hepatocellular carcinoma, has not been fully achieved. Scope of review: This article briefly outlines the previously proposed hypotheses on the etiology of the HIR paradox. It then discusses literature consistent with an alternative hypothesis that excessive gluconeogenesis, the direct effect of HIR, is responsible for the aberrant lipogenesis. The mechanisms involved therein are explained, involving de novo synthesis of fructose and uric acid, promotion of glutamine anaplerosis, and induction of glucagon resistance. Thus, gluconeogenesis via lipogenesis promotes hepatic steatosis, a component of NAFLD, and dyslipidemia. Gluconeogenesis-centred mechanisms for the progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis are suggested. That NAFLD often precedes and predicts type 2 diabetes is explained by the ability of lipogenesis to cushion against blood glucose dysregulation in the earlier stages of NAFLD. Major conclusions: HIR-induced excessive gluconeogenesis is a major cause of the HIR paradox and its sequelae. Such involvement of gluconeogenesis in lipid synthesis rationalizes the fact that several types of antidiabetic drugs ameliorate NAFLD. Thus, dietary, lifestyle and pharmacological targeting of HIR and hepatic gluconeogenesis may be a most viable approach for the prevention and management of the HIR-associated network of diseases.

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]

Glucoselysine (GL) is an unique advanced glycation end-product derived from fructose. The main source of fructose in vivo is the polyol pathway, and an increase in its activity leads to diabetic complications. Here, we aimed to demonstrate that GL can serve as an indicator of the polyol pathway activity. Additionally, we propose a novel approach for detecting GL in peripheral blood samples using liquid chromatography-tandem mass spectrometry and evaluate its clinical usefulness. We successfully circumvent interference from fructoselysine, which shares the same molecular weight as GL, by performing ultrafiltration and hydrolysis without reduction, successfully generating adequate peaks for quantification in serum. Furthermore, using immortalized aldose reductase KO mouse Schwann cells, we demonstrate that GL reflects the downstream activity of the polyol pathway and that GL produced intracellularly is released into the extracellular space. Clinical studies reveal that GL levels in patients with type 2 diabetes are significantly higher than those in healthy participants, while N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1) levels are significantly lower. Both GL and MG-H1 show higher values among patients with vascular complications; however, GL varies more markedly than MG-H1 as well as hemoglobin A1c, fasting plasma glucose, and estimated glomerular filtration rate. Furthermore, GL remains consistently stable under various existing drug treatments for type 2 diabetes, whereas MG-H1 is impacted. To the best of our knowledge, we provide important insights in predicting diabetic complications caused by enhanced polyol pathway activity via assessment of GL levels in peripheral blood samples from patients., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Spinal cord contusion injury leads to Wallerian degeneration of axonal tracts, resulting in irreversible paralysis. Contusion injury causes perfusion loss by thrombosis and vasospasm, resulting in spinal cord ischemia. In several tissues, including heart and brain, ischemia activates polyol pathway enzymes?aldose reductase (AR) and sorbitol dehydrogenase (SDH)?that convert glucose to sorbitol and fructose in reactions, causing oxidative stress and tissue loss. We sought to determine whether activation of this pathway, which has been termed glucotoxicity, contributes to tissue loss after spinal cord contusion injury. We tested individual treatments with AR inhibitors (sorbinil or ARI-809), SDH inhibitor (CP-470711), superoxide dismutase mimetic (tempol), or combined sorbinil and tempol. Each treatment significantly increased locomotor recovery and reduced loss of spinal cord tissue in a standard model of spinal cord contusion in rats. Tissue levels of sorbitol and axonal AR (AKR1B10) expression were increased after contusion injury, consistent with activation of the polyol pathway. Sorbinil treatment inhibited the above changes and also decreased axonal swelling and loss, characteristic of Wallerian degeneration. Treatment with tempol induced recovery of locomotor function that was similar in magnitude, but non-additive to sorbinil, suggesting a shared mechanism of action by reactive oxygen species (ROS). Exogenous induction of hyperglycemia further increased injury-induced axonal swelling, consistent with glucotoxicity. Unexpectedly, contusion increased spinal cord levels of glucose, the primary polyol pathway substrate. These results support roles for spinal glucose elevation and tissue glucotoxicity by the polyol pathway after spinal cord contusion injury that results in ROS-mediated axonal degeneration.

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.

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]

• ALR2, 1st enzyme of polyol pathway, overactives in diabetics, driving complications. • Strategies for managing diabetic complications via ALR2 targeting are exemplified. • Target-level selectivity challenges hindering ALR2 inhibition have been discussed. • Comparative SAR investigations for selectively targeting ALR2 inhibitors over ALR1. • In-depth interaction analysis to illustrate the target selective binding features. Chronic hyperglycemia initiates multiple pathways that contribute to developing complications in individuals with diabetes, ultimately leading to significant health problems and mortality. The extensive research elucidated the pathophysiological role of aldose reductase (ALR2) in the polyol pathway, which significantly contributes to these diabetic complications. ALR2, a rate-limiting enzyme in this pathway, becomes overactive in hyperglycemic conditions and plays a central role in developing diabetic complications. As a result, inhibiting ALR2 has emerged as a promising approach for managing these complications. Despite numerous ALR2 inhibitors, only epalrestat is currently marketed, mainly due to challenges related to their limited selectivity for ALR2 over aldehyde reductase (ALR1). This selectivity issue arises because ALR2 shares 65 % structural similarity with ALR1, leading to concerns about potential toxicity. This article provides a detailed overview of the advancements made in the last decade (2012–2023) in developing ALR2 and ALR1 inhibitors, addressing the selectivity challenges between ALR2 and ALR1 through comparative structure-activity relationship (SAR) analyses. It also explores the intricate interactions of potent ligands within the catalytic sites of both ALR2 and ALR1, offering innovative strategies for designing target-specific ALR2 inhibitors to minimize off-target toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Aldose reductase is a member of the 1B1 subfamily of aldo-keto reductase gene superfamily. The action of aldose reductase (AR) has been implicated in the pathogenesis of a variety of disease states, most notably complications of diabetes mellitus including neuropathy, retinopathy, nephropathy, and cataracts. To explore for mechanistic roles for AR in disease pathogenesis, we established mutant strains produced using Crispr-Cas9 to inactivate the AKR1B3 gene in C57BL6 mice. Phenotyping AR-knock out (ARKO) strains confirmed previous reports of reduced accumulation of tissue sorbitol levels. Lens epithelial cells in ARKO mice showed markedly reduced epithelial-to-mesenchymal transition following lens extraction in a surgical model of cataract and posterior capsule opacification. A previously unreported phenotype of preputial sebaceous gland swelling was observed frequently in male ARKO mice homozygous for the mutant AKR1B3 allele. This condition, which was shown to be accompanied by infiltration of proinflammatory CD3+ lymphocytes, was not observed in WT mice or mice heterozygous for the mutant allele. Despite this condition, reproductive fitness of the ARKO strain was indistinguishable from WT mice housed under identical conditions. These studies establish the utility of a new strain of AKR1B3-null mice created to support mechanistic studies of cataract and diabetic eye disease. • AKR1B3-null mice (ARKO) were produced by Crispr-Cas9-mediated gene disruption. • ARKO mice demonstrate reduced EMT response following lens extraction. • ARKO mice are at increased risk for development of preputial gland inflammation. [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.

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]

Background: Lots of plants in genus Swertia are widely used in the traditional medicine as the treatment for T2DM and its complications in Asia. However, the pharmacodynamic material basis and underlying mechanisms of these plants are still incompletely studied. Inhibition of aldose reductase to regulate polyol pathway is considered to be one effective strategy to treat many complications arising from diabetes. Aim: The inhibitory effect against aldose reductase of typical components from the genus Swertia were examined, and further verified in db/db mice model to explore its in vivo renal protective ability and underlying mechanism. Methods: Human recombinant aldose reductase (AR) was applied to detect the inhibitory activity of these components from genus Swetia in vitro, and the most active one was further analyzed in molecular docking experiment. Then, db/db diabetic mice model were employed to investigate the renal protective effects in vivo. Oxidative stress and renal function related indicators were determined using biochemical kit. Histopathological examination of kidney was conducted to evaluate pathological variations. RT-PCR was applied to measure the level of AR mRNA in renal cortex. Expression of AR, TGF-β1, Collagen Ⅳ, Nephrin and Podocin in kidney tissues were assessed by Western blot. Results: It turned out that demethylbellidifolin (DMB) showed the strongest inhibitory activity against AR, with an IC50 of 1.29 ± 0.16 μM, by stabilizing the active site of AR. In vivo experiment confirmed that DMB could remarkably reduce blood glucose and albuminuria level, and alleviate oxidative stress response. Meanwhile, histopathological examination also displayed that the kidney damage in db/db mice was significantly improved after treatment with DMB. Further mechanism study indicated that DMB could prevent the accumulation of sorbitol, one of the polyol pathway products. Besides, DMB could also maintaining the integrity of podocytes structure by up-regulating the expression of Nephrin and Podocin, and exert renal protective effects by inhibiting the expression of AR, Collagen Ⅳ and TGF-β1 in the polyol pathway. Conclusions: These findings indicated that genus Swertia could be an important plant sources of aldose reductase inhibitors, and one of its typical components, DMB, exerted a therapeutic role in the treatment of diabetic nephropathy by regulating the polyol pathway to relieve the injury of cells in the kidney, and may represent a promising renal protective medication for diabetic nephropathy therapy.

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]