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1
Thaifa, M.S, Kumar Manoj, U.S Arya, and G. Babu Aparna. "Diabetic Nephropathy: A Plant Based Approach." Endocrinology & Metabolic Syndrome 10, no. 6 (2021): 3. https://doi.org/10.5281/zenodo.10362117.
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Diabetic nephropathy is a complication associated with diabetes mellitus. Diabetes mellitus is a chronic metabolic disorder caused by impaired metabolism of carbohydrate, fats, proteins resulting in hyperglycaemia leading to decreased utilization of carbohydrate, excessive glycogenolysis and gluconeogenesis from amino acids and fatty acids. Diabetic nephropathy is a kidney disease induced by diabetes and occurs due to high blood sugar in the kidney. Keywords: Diabetic nephropathy; Polyol pathway; Hyperglycaemia
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Wada, Jun, and Hirofumi Makino. "Inflammation and the pathogenesis of diabetic nephropathy." Clinical Science 124, no. 3 (2012): 139–52. http://dx.doi.org/10.1042/cs20120198.
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The most problematic issue in clinical nephrology is the relentless and progressive increase in patients with ESRD (end-stage renal disease) worldwide. The impact of diabetic nephropathy on the increasing population with CKD (chronic kidney disease) and ESRD is enormous. Three major pathways showing abnormality of intracellular metabolism have been identified in the development of diabetic nephropathy: (i) the activation of polyol and PKC (protein kinase C) pathways; (ii) the formation of advanced glycation end-products; and (iii) intraglomerular hypertension induced by glomerular hyperfiltration. Upstream of these three major pathways, hyperglycaemia is the major driving force of the progression to ESRD from diabetic nephropathy. Downstream of the three pathways, microinflammation and subsequent extracellular matrix expansion are common pathways for the progression of diabetic nephropathy. In recent years, many researchers have been convinced that the inflammation pathways play central roles in the progression of diabetic nephropathy, and the identification of new inflammatory molecules may link to the development of new therapeutic strategies. Various molecules related to the inflammation pathways in diabetic nephropathy include transcription factors, pro-inflammatory cytokines, chemokines, adhesion molecules, Toll-like receptors, adipokines and nuclear receptors, which are candidates for the new molecular targets for the treatment of diabetic nephropathy. Understanding of these molecular pathways of inflammation would translate into the development of anti-inflammation therapeutic strategies.
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Pisoschi, Catalina, Virgil Darie, and Mihai Serban. "STUDY OF RENAL SORBITOLDEHYDROGENASE IN EXPERIMENTAL DIABETIC NEPHROPATHY." SOUTHERN BRAZILIAN JOURNAL OF CHEMISTRY 6, no. 7 (1998): 77–82. http://dx.doi.org/10.48141/sbjchem.v6.n7.1998.76_1998_2.pdf.
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The link between the polyol pathway and the ocular complications of diabetes mellitus is explained by the excessive storage of sorbitol and the release of osmotic stress. The renal complications could also be explained by the osmotic hypothesis, but the polyol pathway activity is reduced in this case. The study of sorbitol dehydrogenase (SDH) activity, one of the enzymes involved in the catabolism of glucose by this pathway in renal and hepatic homogenates from diabetic animals, shows a constant increase of the hepatic enzyme activity compared to that at the renal level. The different variations of the renal SDH activity can be explained by the effect of hyperglycemia on the active form of the enzyme and its inactivation by nonenzymatic glycosylation.
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Zhang, Yunfang, Junxia Feng, Qi Wang, et al. "Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis." Cellular Physiology and Biochemistry 51, no. 4 (2018): 1778–98. http://dx.doi.org/10.1159/000495681.
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Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.
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Kuklin, V. N., J. Matri, N. P. Barlow, et al. "Current trends in management of hyperglycaemia in surgical patients with diabetes mellitus: a review." Annals of critical care, no. 4 (2021): 33–47. http://dx.doi.org/10.21320/1818-474x-2021-4-33-47.
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A large amount of clinical evidences demonstrates a clear association between long-term and/or stress-related hyperglycaemia, and development of complications after surgery. The incidences of perioperative hyperglycaemia are demonstrated in 20-80 % of all cases depending on the type of elective surgery, with the h ighest rate registered in cardiac surgery. The most studied pathophysiological complications of long-term hyperglycaemia in Diabetes Mellitus (DM) patients are; activation of the polyol pathway, diacylglycerol/protein kinase C and hexosamine pathways, advanced glycation product formation, and oxidative stress. The uncontrolled stress-related hyperglycaemia during and after surgery instigates: osmotic diuresis with further fluid and electrolyte imbalance, increased gluconeogenesis and glucogenolysis, breakdown of fats into free fatty acid and glycerol, proteins into amino acids, and increases generation of pro-inflammatory cytokines. All these changes may lead to development of diabetic ketoacidosis, immune deregulation and insulin resistance. Some clinical investigations seems to indicate that anaesthesia with propofol may have some advantages in keeping of stable blood sugar over inhalational agents. Two clinical trials comparing the influence of different anaesthetic agents on perioperative glycaemic status in diabetic patients are currently underway. For better management of perioperative hyperglycaemia in diabetic patients under surgery we have proposed several important practical principles.
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Tsugawa, T., R. Shinohara, A. Nagasaka, et al. "Alteration of urinary sorbitol excretion in WBN-kob diabetic rats - treatment with an aldose reductase inhibitor." Journal of Endocrinology 181, no. 3 (2004): 429–35. http://dx.doi.org/10.1677/joe.0.1810429.
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An accelerated polyol pathway in diabetes contributes to the development of diabetic complications. To elucidate diabetic nephropathy involving also renal tubular damage, we measured urinary sorbitol concentration concomitantly with urinary N-acetyl-D-glucosaminidase (NAG) excretion in WBN-kob diabetic rats.Twenty-four-hour urinary sorbitol concentrations increased in the diabetic rats in parallel with whole blood sorbitol concentrations. An increase in 24-h urinary NAG excretion coincided with the elevated urinary sorbitol levels in the diabetic rats. The administration of epalrestat, an aldose reductase inhibitor, reduced the increased whole blood and urinary sorbitol concentrations and urinary NAG excretion concomitantly with renal aldose reductase inhibition in the diabetic rats.These results indicate that diabetic nephropathy involves distorted cell function of renal tubules, and that treatment with epalrestat may prevent at least the progress of the nephropathy.
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Isermann, Berend H., Hongjie Wang, Peter P. Nawroth, and Thati Madhusudhan. "Activated Protein C Targets PI3K-p85/XBP1 Pathway to Inhibit Hyperglycemia Induced Endoplasmic Reticulum Stress in Diabetic Nephropathy." Blood 120, no. 21 (2012): 3354. http://dx.doi.org/10.1182/blood.v120.21.3354.3354.
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Abstract Abstract 3354 Diabetic nephropathy (DN) is a multifactorial disease associated with substantial changes in the haemostatic system. A hallmark of diabetes induced haemostatic dysfunction is impaired thrombomodulin (TM) dependent-protein C (PC) activation. Impaired PC activation triggers glomerular podocyte and endothelial cell dysfunction, thus promoting DN. The intracellular mechanism through which loss of TM and PC activation contributes to DN is not known. Here we show that the haemostatic mediator activated PC (aPC) regulates cellular homeostasis by inhibiting hyperglycemia induced endoplasmic reticulum (ER)-stress in DN. Hyperglycaemia was induced in wild-type (wt) mice or mice with altered activity of the TM-PC system (loss of function secondary to impaired PC activation (TMPro/LacZ) or gain of function with high aPC plasma levels (APChigh)). Subsets of diabetic mice were treated with the chemical ER-chaperone TUDCA. After 26 weeks of persistent hyperglycaemia markers of DN were determined and tissue samples were isolated for ex vivo analysis. Supplementary in vitro assays were performed in podocytes and endothelial cells. Persistent hyperglycaemia in wt mice caused severe ER-stress and DN. Ex vivo analysis of transcription factors regulating the ER-stress response showed an increase of the ER-stress markers CHOP and ATF6, while nuclear translocation of the highly conserved transcription factor X-box binding protein-1 (XBP1) was reduced in DN. These changes were aggravated in diabetic TMPro/LacZ mice. Conversely, in a mouse model with constitutively higher aPC levels (APChigh mice) nuclear levels of XBP1 were normalized and expression of ATF6 and CHOP was reduced despite persistent hyperglycaemia. In addition, aPC reverses the pathological ER-stress alterations in diabetic TMPro/LacZ mice. Pharmacological inhibition of ER-stress by TUDCA normalized nuclear levels of XBP1, inhibited CHOP/ATF6 expression, and protected against DN in diabetic wt and TMPro/LacZ mice. In vitro hyperglycaemia inhibited nuclear translocation of XBP1 in endothelial cells and podocytes, the two cellular components of glomerular filtration barrier. Activated PC directly promotes the nuclear translocation of XBP1 in these cells, which is required to inhibit hyperglycaemia induced ER-stress. Deletion of XBP1 in podocyte or endothelial cells abolished the cytoprotective effect of aPC. Furthermore, aPC regulates the interaction of PI3K regulatory subunit p85α with XBP1 which is known to mediate its nuclear translocation and diminished hyperglycaemia induced ER-stress. These studies demonstrate that hyperglycemia induced ER-stress is causally linked to DN and establish a novel link between haemostatic system and ER function in regulating cellular homeostasis in chronic kidney disease. Disclosures: No relevant conflicts of interest to declare.
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Dunlop, Marjorie. "Aldose reductase and the role of the polyol pathway in diabetic nephropathy." Kidney International 58 (September 2000): S3—S12. http://dx.doi.org/10.1046/j.1523-1755.2000.07702.x.
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Tarr, Joanna M., Kirti Kaul, Mohit Chopra, Eva M. Kohner, and Rakesh Chibber. "Pathophysiology of Diabetic Retinopathy." ISRN Ophthalmology 2013 (January 15, 2013): 1–13. http://dx.doi.org/10.1155/2013/343560.
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Diabetes is now regarded as an epidemic, with the population of patients expected to rise to 380 million by 2025. Tragically, this will lead to approximately 4 million people around the world losing their sight from diabetic retinopathy, the leading cause of blindness in patients aged 20 to 74 years. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure, and possibly lipids. Although landmark cross-sectional studies have confirmed the strong relationship between chronic hyperglycaemia and the development and progression of diabetic retinopathy, the underlying mechanism of how hyperglycaemia causes retinal microvascular damage remains unclear. Continued research worldwide has focussed on understanding the pathogenic mechanisms with the ultimate goal to prevent DR. The aim of this paper is to introduce the multiple interconnecting biochemical pathways that have been proposed and tested as key contributors in the development of DR, namely, increased polyol pathway, activation of protein kinase C (PKC), increased expression of growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), haemodynamic changes, accelerated formation of advanced glycation endproducts (AGEs), oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and subclinical inflammation and capillary occlusion. New pharmacological therapies based on some of these underlying pathogenic mechanisms are also discussed.
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Marrero, Mario B., Amy K. Banes-Berceli, David M. Stern, and Douglas C. Eaton. "Role of the JAK/STAT signaling pathway in diabetic nephropathy." American Journal of Physiology-Renal Physiology 290, no. 4 (2006): F762—F768. http://dx.doi.org/10.1152/ajprenal.00181.2005.
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Excessive cellular growth is a major contributor to pathological changes associated with diabetic nephropathy. In particular, high glucose-induced growth of glomerular mesangial cells is a characteristic feature of diabetes-induced renal complications. Glomerular mesangial cells respond to traditional growth factors, although in diabetes this occurs in the context of an environment enriched in both circulating vasoactive mediators and high glucose. For example, the vasoactive peptide ANG II has been implicated in the pathogenesis of diabetic renal disease, and recent findings suggest that high glucose and ANG II activate intracellular signaling processes, including the polyol pathway and generation of reactive oxygen species. These pathways activate the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascades in glomerular mesangial cells. Activation of the JAK/STAT signaling cascade can stimulate excessive proliferation and growth of glomerular mesangial cells, contributing to diabetic nephropathy. This review focuses on some of the key elements in the diabetic microenvironment, especially high glucose and the accumulation of advanced glycoxidation end products and considers their impact on ANG II and other vasoactive peptide-mediated signaling events in vitro and in vivo.
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Grewal, Ajmer Singh, Komal Thapa, Neha Kanojia, Neelam Sharma, and Sukhbir Singh. "Natural Compounds as Source of Aldose Reductase (AR) Inhibitors for the Treatment of Diabetic Complications: A Mini Review." Current Drug Metabolism 21, no. 14 (2020): 1091–116. http://dx.doi.org/10.2174/1389200221666201016124125.
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Background: Aldol reductase (AR) is the polyol pathway's main enzyme that portrays a crucial part in developing ‘complications of diabetes’ involving cataract, retinopathy, nephropathy, and neuropathy. These diabetic abnormalities are triggered tremendously via aggregation of sorbitol formation (catalyzed by AR) in the polyol pathway. Consequently, it represents an admirable therapeutic target and vast research was done for the discovery of novel molecules as potential AR inhibitors for diabetic complications. Objective: This review article has been planned to discuss an outline of diabetic complications, AR and its role in diabetic complications, natural compounds reported as AR inhibitors, and benefits of natural/plant derived AR inhibitors for the management of diabetic abnormalities. Results: The goal of AR inhibition remedy is to stabilize the increased flux of blood glucose and sorbitol via the ‘polyol pathway’ in the affected tissues. A variety of synthetic inhibitors of AR have been established such as tolrestat and sorbinil, but both of these face limitations including low permeability and health problems. Pharmaceutical industries and other scientists were also undertaking work to develop newer, active, and ‘safe’ AR inhibitors from natural sources. Therefore, several naturally found molecules were documented to possess a potent inhibitory action on AR activity. Conclusion: Natural inhibitors of AR appeared as harmless pharmacological agents for controlling diabetic complications. The detailed literature throughout this article shows the significance of herbal extracts and phytochemicals as prospective useful AR inhibitors in treating diabetic complications.
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Simran, Amarjot Kaur Grewal, Sandeep Arora, and Thakur Gurjeet Singh. "Role of Protein Kinase C in Diabetic Complications." Journal of Pharmaceutical Technology, Research and Management 7, no. 2 (2019): 87–95. http://dx.doi.org/10.15415/jptrm.2019.72011.
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Diabetes is the most common and systemic disorder associated with hyperglycemia which is the significant factor in the development of micro- and macrovascular changes. Many mechanistic approaches i.e. activation of Protein kinase C, glycation end products production, hexosamine pathway and polyol pathway induce cellular damage and lead to the development of diabetic complications like nephropathy, neuropathy, retinopathy, and myopathy. One of the adverse effects of long-lasting hyperglycemia is activation of PKC (intracellular signaling enzyme) and has become a field of great research interest. Hence, in this review special emphasis is placed on microvascular complications which are due to activation of PKC. Clinical trials have also been conducted using selective PKC inhibitors and have shown positive results against hyperglycemia.
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Kafle, D., N. Islam, B. Aryal, P. Adhikary, and Neelina Singh. "Inflammation and Oxidative Stress via Persistent Hyperglycemia in Progression of Diabetic Nephropathy in Type 2 Diabetes Mellitus." Journal of Chitwan Medical College 3, no. 1 (2013): 1–4. http://dx.doi.org/10.3126/jcmc.v3i1.8456.
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Diabetic nephropathy is a major microvascular complication of diabetes, representing the leading cause of end stage renal disease in the world, and a major cause of morbidity and mortality in type 2 diabetic subjects. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD (P) H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. Changes in oxidative stress biomarkers, including superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione levels, vitamins, lipid peroxidation, nitrite concentration, nonenzymatic glycosylated proteins have been associated with diabetic nephropathy due to oxidative stress induced hyperglycemia. Oxidative stress in diabetes is responsible for endothelial dysfunction releasing inflammatory markers cytokines from the damaged renal tissue. Hyperglycemia induces intracellular reactive oxygen species in mesangial and tubular epithelial cells which induces cytokines, IL-6 and TNF-α production in glomerular mesangial and tubular epithelial cells in diabetic kidney. Antioxidants inhibit high glucose induced transforming growth factors and extra cellular matrix expression in glomerular mesangial and tubular epithelial cells, which ameliorate features of diabetic nephropathy, suggesting that oxidative stress plays an important role in diabetic renal injury causing diabetic nephropathy. Journal of Chitwan Medical College 2013; 3(1): 1-4 DOI: http://dx.doi.org/10.3126/jcmc.v3i1.8456
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Xie, Haifei, Qilin Tong, Zhinan Xiang, Chenggao Zhou, Luo-Sheng Wan, and Jiachun Chen. "Demethylbellidifolin, a potential aldose reductase inhibitor ameliorates diabetic nephropathy by regulating the polyol pathway." Phytomedicine Plus 2, no. 1 (2022): 100152. http://dx.doi.org/10.1016/j.phyplu.2021.100152.
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Safar, Marwa M., and Rania M. Abdelsalam. "H2S donors attenuate diabetic nephropathy in rats: Modulation of oxidant status and polyol pathway." Pharmacological Reports 67, no. 1 (2015): 17–23. http://dx.doi.org/10.1016/j.pharep.2014.08.001.
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Zhou, Xiaoyu, Zheng Liu, Ke Ying, et al. "WJ-39, an Aldose Reductase Inhibitor, Ameliorates Renal Lesions in Diabetic Nephropathy by Activating Nrf2 Signaling." Oxidative Medicine and Cellular Longevity 2020 (May 30, 2020): 1–21. http://dx.doi.org/10.1155/2020/7950457.
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Diabetic nephropathy (DN) is a chronic diabetic microvascular complication. Hyperactivity of the polyol pathway is involved in the pathogenesis of DN. Aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, is expected to be an effective target in the treatment of DN. WJ-39 is a novel inhibitor of AR. The present study aimed at exploring the effects of WJ-39 in DN. DN was induced in rats by injecting 30 mg/kg streptozotocin (STZ). After 14 weeks, WJ-39 (10, 20, and 40 mg/kg) was intragastrically administered to the rats for 12 weeks. Treatment with WJ-39 significantly inhibited AR activation and ameliorated renal dysfunction and fibrosis in DN rats. WJ-39 reduced oxidative stress in the kidneys of DN rats by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. WJ-39 suppressed the activation of the nuclear factor-kappa B (NF-κB) pathway and the nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome to reduce the secretion of inflammatory factors. Rat mesangial cells (RMCs) were cultured under hyperglycemic conditions. WJ-39 abrogated the high glucose- (HG-) induced, excessive production of reactive oxygen species (ROS) and inflammatory factors. However, transfection with Nrf2 small interfering RNA abolished the effects of WJ-39. WJ-39 also blocked the transforming growth factor-β1/Smad pathway to reduce the production of glomerular extracellular matrix proteins, ultimately reducing fibrogenesis in DN. Our results show that WJ-39 ameliorated renal injury in DN rats, and its effects on oxidative stress and inflammation were associated with the activation of Nrf2 signaling. Thus, WJ-39 and its mechanism of amelioration of renal lesions in DN rats by reducing renal inflammation, oxidative stress, and fibrosis injury could be an effective strategy for the treatment of DN.
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Lane, Pascale H. "Diabetic kidney disease: impact of puberty." American Journal of Physiology-Renal Physiology 283, no. 4 (2002): F589—F600. http://dx.doi.org/10.1152/ajprenal.00368.2001.
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Puberty accelerates microvascular complications of diabetes mellitus, including nephropathy. Animal studies confirm a different renal hypertrophic response to diabetes before and after puberty, probably due to differences in the production of transforming growth factor-β (TGF-β). Many of the complex physiological changes during puberty could affect potentially pathogenic mechanisms of diabetic kidney disease. Increased blood pressure, activation of the growth hormone-insulin-like growth factor I axis, and production of sex steroids could all play a role in pubertal susceptibility to diabetic renal hypertrophy and nephropathy. These factors may influence the effects of hyperglycemia and several systems that ultimately control TGF-β production, including the renin-angiotensin system, cellular redox systems, the polyol pathway, and protein kinase C. These phenomena may also explain gender differences in kidney function and incidence of end-stage renal disease. Normal changes during puberty, when coupled with diabetes and superimposed on a genetically susceptible milieu, are capable of accelerating diabetic hypertrophy and microvascular lesions. A better understanding of these processes may lead to new treatments to prevent renal failure in diabetes mellitus.
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Thorne, Courtney A., Angus C. Grey, Julie C. Lim, and Paul J. Donaldson. "The Synergistic Effects of Polyol Pathway-Induced Oxidative and Osmotic Stress in the Aetiology of Diabetic Cataracts." International Journal of Molecular Sciences 25, no. 16 (2024): 9042. http://dx.doi.org/10.3390/ijms25169042.
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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.
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Ren, Chaoxing, Xiaowei Zhou, Xiaowen Bao, et al. "Dioscorea zingiberensis ameliorates diabetic nephropathy by inhibiting NLRP3 inflammasome and curbing the expression of p66Shc in high-fat diet/streptozotocin-induced diabetic mice." Journal of Pharmacy and Pharmacology 73, no. 9 (2021): 1218–29. http://dx.doi.org/10.1093/jpp/rgab053.
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Abstract Objectives Diabetic nephropathy (DN) is a severe diabetic complication. Dioscorea zingiberensis (DZ) possesses excellent pharmacological properties with lower toxicity. The purpose of this study was to investigate the efficacy and mechanism of DZ in DN. Methods DN was established by the high-fat diet combining intraperitoneal injection of streptozotocin in mice. The DZ (125 and 250 mg/kg/day) were intragastrical administered for 8 consecutive weeks. After treatment, blood, urine and kidney tissue were collected for biological detection, renal morphology, fibrosis and molecular mechanism research, respectively. Key findings This study has shown that DZ significantly ameliorated kidney hypertrophy, renal structural damage and abnormal function of the kidney indicators (creatinine, urinary protein and blood urea nitrogen). Further molecular mechanism data suggested that the NLRP3/Cleaved-caspase-1 signal pathway was remarkably activated in DN, and DZ treatment reversed these changes, which indicated that it effectively attenuated inflammatory response caused by hyperglycaemia. In addition, DN inhibits hyperglycaemia-induced activation of oxidative stress by suppressing the expression of p66Shc proteins. Conclusions DZ could efficiently suppress oxidative stress and inflammatory responses to postpone the development of DN, and its mechanism might be related to inhibition of NLRP3 and p66Shc activities. Thus, DZ could be developed into a new therapeutic agent for DN.
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Balestri, Francesco, Roberta Moschini, Umberto Mura, Mario Cappiello, and Antonella Del Corso. "In Search of Differential Inhibitors of Aldose Reductase." Biomolecules 12, no. 4 (2022): 485. http://dx.doi.org/10.3390/biom12040485.
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Aldose reductase, classified within the aldo-keto reductase family as AKR1B1, is an NADPH dependent enzyme that catalyzes the reduction of hydrophilic as well as hydrophobic aldehydes. AKR1B1 is the first enzyme of the so-called polyol pathway that allows the conversion of glucose into sorbitol, which in turn is oxidized to fructose by sorbitol dehydrogenase. The activation of the polyol pathway in hyperglycemic conditions is generally accepted as the event that is responsible for a series of long-term complications of diabetes such as retinopathy, cataract, nephropathy and neuropathy. The role of AKR1B1 in the onset of diabetic complications has made this enzyme the target for the development of molecules capable of inhibiting its activity. Virtually all synthesized compounds have so far failed as drugs for the treatment of diabetic complications. This failure may be partly due to the ability of AKR1B1 to reduce alkenals and alkanals, produced in oxidative stress conditions, thus acting as a detoxifying agent. In recent years we have proposed an alternative approach to the inhibition of AKR1B1, suggesting the possibility of a differential inhibition of the enzyme through molecules able to preferentially inhibit the reduction of either hydrophilic or hydrophobic substrates. The rationale and examples of this new generation of aldose reductase differential inhibitors (ARDIs) are presented.
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Hashimoto, Yasuhiro, Shin-Ichiro Yamagishi, Hiroki Mizukami, et al. "Polyol pathway and diabetic nephropathy revisited: Early tubular cell changes and glomerulopathy in diabetic mice overexpressing human aldose reductase." Journal of Diabetes Investigation 2, no. 2 (2010): 111–22. http://dx.doi.org/10.1111/j.2040-1124.2010.00071.x.
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Wang, Tianyang, Xuejiao Wen, Ziwen Zhang, Minjuan Xie та Jie Zhou. "Phillyrin ameliorates diabetic nephropathy through the PI3K/Akt/GSK-3β signalling pathway in streptozotocin-induced diabetic mice". Human & Experimental Toxicology 40, № 12_suppl (2021): S487—S496. http://dx.doi.org/10.1177/09603271211051598.
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Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3β (GSK-3β) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3β pathway.
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Laustsen, Christoffer, Per Mose Nielsen, Thomas Stokholm Nørlinger, et al. "Antioxidant treatment attenuates lactate production in diabetic nephropathy." American Journal of Physiology-Renal Physiology 312, no. 1 (2017): F192—F199. http://dx.doi.org/10.1152/ajprenal.00148.2016.
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The early progression of diabetic nephropathy is notoriously difficult to detect and quantify before the occurrence of substantial histological damage. Recently, hyperpolarized [1-13C]pyruvate has demonstrated increased lactate production in the kidney early after the onset of diabetes, implying increased lactate dehydrogenase activity as a consequence of increased nicotinamide adenine dinucleotide substrate availability due to upregulation of the polyol pathway, i.e., pseudohypoxia. In this study, we investigated the role of oxidative stress in mediating these metabolic alterations using state-of-the-art hyperpolarized magnetic resonance (MR) imaging. Ten-week-old female Wistar rats were randomly divided into three groups: healthy controls, untreated diabetic (streptozotocin treatment to induce insulinopenic diabetes), and diabetic, receiving chronic antioxidant treatment with TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) via the drinking water. Examinations were performed 2, 3, and 4 wk after the induction of diabetes by using a 3T Clinical MR system equipped with a dual tuned 13C/1H-volume rat coil. The rats received intravenous hyperpolarized [1-13C]pyruvate and were imaged using a slice-selective 13C-IDEAL spiral sequence. Untreated diabetic rats showed increased renal lactate production compared with that shown by the controls. However, chronic TEMPOL treatment significantly attenuated diabetes-induced lactate production. No significant effects of diabetes or TEMPOL were observed on [13C]alanine levels, indicating an intact glucose-alanine cycle, or [13C]bicarbonate, indicating normal flux through the Krebs cycle. In conclusion, this study demonstrates that diabetes-induced pseudohypoxia, as indicated by an increased lactate-to-pyruvate ratio, is significantly attenuated by antioxidant treatment. This demonstrates a pivotal role of oxidative stress in renal metabolic alterations occurring in early diabetes.
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Whiteside, Catharine I., and John A. Dlugosz. "Mesangial cell protein kinase C isozyme activation in the diabetic milieu." American Journal of Physiology-Renal Physiology 282, no. 6 (2002): F975—F980. http://dx.doi.org/10.1152/ajprenal.00014.2002.
Full textAbstract:
High-glucose-induced activation of mesangial cell protein kinase C (PKC) contributes significantly to the pathogenesis of diabetic nephropathy. Excess glucose metabolism through the polyol pathway leads to de novo synthesis of both diacylglyerol (DAG) and phosphatidic acid, which may account for increased mesangial cell PKC-α, -β, -δ, -ε, and -ζ activation/translocation observed within 48-h exposure to high glucose. Raised intracellular glucose causes generation of reactive oxygen species that may directly activate PKC isozymes and enhance their reactivity to vasoactive peptide signaling. In both diabetic rodent models of diabetes and cultured mesangial cells, PKC-β appears to be the key isozyme required for the enhanced expression of transforming growth factor-β1, initiation of early accumulation of mesangial matrix protein, and increased microalbuminuria. Enhanced collagen IV expression by mesangial cells in response to vasoactive peptide hormone stimulation, e.g., endothelin-1, requires PKC-β, -δ, -ε and -ζ. Loss of mesangial cell contractility to potent vasoactive peptides and coincident F-actin disassembly are due to high-glucose-activation of PKC-ζ. Inhibition of mesangial cell PKC isozyme activation in high glucose may prove to be the next important treatment for diabetic nephropathy.
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Singh, Mahavir, Aniruddh Kapoor, and Aruni Bhatnagar. "Physiological and Pathological Roles of Aldose Reductase." Metabolites 11, no. 10 (2021): 655. http://dx.doi.org/10.3390/metabo11100655.
Full textAbstract:
Aldose reductase (AR) is an aldo-keto reductase that catalyzes the first step in the polyol pathway which converts glucose to sorbitol. Under normal glucose homeostasis the pathway represents a minor route of glucose metabolism that operates in parallel with glycolysis. However, during hyperglycemia the flux of glucose via the polyol pathway increases significantly, leading to excessive formation of sorbitol. The polyol pathway-driven accumulation of osmotically active sorbitol has been implicated in the development of secondary diabetic complications such as retinopathy, nephropathy, and neuropathy. Based on the notion that inhibition of AR could prevent these complications a range of AR inhibitors have been developed and tested; however, their clinical efficacy has been found to be marginal at best. Moreover, recent work has shown that AR participates in the detoxification of aldehydes that are derived from lipid peroxidation and their glutathione conjugates. Although in some contexts this antioxidant function of AR helps protect against tissue injury and dysfunction, the metabolic transformation of the glutathione conjugates of lipid peroxidation-derived aldehydes could also lead to the generation of reactive metabolites that can stimulate mitogenic or inflammatory signaling events. Thus, inhibition of AR could have both salutary and injurious outcomes. Nevertheless, accumulating evidence suggests that inhibition of AR could modify the effects of cardiovascular disease, asthma, neuropathy, sepsis, and cancer; therefore, additional work is required to selectively target AR inhibitors to specific disease states. Despite past challenges, we opine that a more gainful consideration of therapeutic modulation of AR activity awaits clearer identification of the specific role(s) of the AR enzyme in health and disease.
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Donnelly, Sandra M., Jannet T. Huang, Xiaopeng P. Zhou, and Catharine I. Whiteside. "Prevention of early glomerulopathy with tolrestat in the streptozotocin-induced diabetic rat." Biochemistry and Cell Biology 74, no. 3 (1996): 355–62. http://dx.doi.org/10.1139/o96-038.
Full textAbstract:
Hyperglycemia is of central importance in the pathogenesis of the complications of diabetes mellitus. Glucose activation of the polyol pathway may lead to renal arteriolar smooth muscle and glomerular mesangial cell hypocontractility. In the streptozotocin-induced diabetic rat, the effect of the aldose reductase inhibitor, tolrestat, in preventing glomerular hyperfiltration, renal hypertrophy, extracellular matrix accumulation, and mesangial cell hypocontractility was addressed. Streptozotocin-induced diabetic rats were followed for 12 weeks and half received tolrestat (25 mg/kg per day). Increased glomerular filtration rate was prevented by tolrestat (3.1 ± 0.3 vs. 1.8 ± 0.2 mL/min, diabetes vs. diabetes + tolrestat, p < 0.01), in part by reduction of the filtration fraction (0.39 ± 0.03 vs. 0.29 ± 0.01, diabetes vs. diabetes + tolrestat, p < 0.01). Tolrestat prevented the raised albumin excretion rates (3594 ± 1154 vs. 713 ± 161 mg/24 h, diabetes vs. diabetes + tolrestat, p < 0.01). Endothelin-1-induced contraction of isolated glomeruli was normal in tolrestat-treated diabetic animals compared with the hypocontractile diabetic glomeruli. Tolrestat prevented glomerular hypertrophy (1.86 ± 0.10 vs. 1.49 ± 0.03 μm2 × 105, diabetes vs. diabetes + tolrestat, p < 0.001) and attenuated the accumulation of basement-membrane-like material (50.2 ± 0.4% vs. 46.4 ± 0.8%, diabetes vs. diabetes + tolrestat, p < 0.001). Fractional mesangial expansion was unchanged in tolrestat-treated diabetic rats compared with untreated animals. Tolrestat prevents the functional changes of glomerular hyperfiltration, mesangial cell hypocontractility, and increased glomerular permeability to albumin. Polyol accumulation may have differential effects on glomerular growth and extracellular matrix accumulation in early diabetic nephropathy.Key words: aldose reductase, nephropathy, renal hemodynamics, renal morphometry, mesangium.
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Sharma, Rahul, and Jaskaran Singh. "New perspectives on markers implicated in signalling pathways that advance diabetic nephropathy and its therapeutic approaches." International Journal of Basic & Clinical Pharmacology 14, no. 1 (2024): 109–16. https://doi.org/10.18203/2319-2003.ijbcp20243845.
Full textAbstract:
Diabetic nephropathy is the chronic loss of kidney function occurring due to diabetes mellitus. Due to increased sugar levels, there is disfunctioning of glomeruli, loss of protein in urine, and decrease in the levels of serum albumin that mainly leads to edema. The progression of renal disfunctioning starts when glomerular filtration rate is greater than 90ml/min. A large body of evidence indicates that oxidative stress is the main attributor involved in the progression of macro-vascular complications of diabetes. (ROS), NAD(P)H oxidase, advanced glycation end products (AGE), polyol pathway, uncoupled nitric oxide synthase (NOS), mitochondrial respiratory chain via oxidative phosphorylation, protein kinase C, mitogen-activated protein kinases, cytokines and transcription factors eventually cause increased expression of extracellular matrix (EC) genes with progression to fibrosis and end stage renal disease. Apart from these well-established pathways, major markers in the kidney disease which could work as potential targets has been explored like MCP-1, BMP-7, p38 MAPK, MiR-130b, HSP-27, AKT which further needs more research as they have shown promising results in their early level of studies. The present review aims to investigate the molecular targets involved in diabetic nephropathy, and to comprehend the intricate signalling pathways, such as JAK/STAT, BMP-7–Smad1/5/8 pathway, RhoA/ROCK, caspases, to which the aforementioned markers have either an independent or dependent relationship. If these signalling pathways are properly studied, these markers may aid in the treatment of the disease and its associated secondary effects such as nephropathy.
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Komal, Chavan Kavita Kulkarni Rahul Mhaske. "A Review Article On Diabetic Neuropathy." International Journal in Pharmaceutical Sciences 2, no. 10 (2024): 1183–86. https://doi.org/10.5281/zenodo.13958273.
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Neuropathy is the most common complication of diabetes. As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end-products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors. Although these metabolic aberrations are deemed as the main stream for the pathogenesis of diabetic microvascular complications, organ-specific histological and biochemical characteristics constitute distinct mechanistic processes of neuropathy different from retinopathy or nephropathy. Heart rate variability (HRV) is an important tool to analyze the autonomic function. It there- fore has a special interest for early detection and ensuing treatment of autonomic neuropathy in diabetic patients. The aim of this work is to present a brief historical review of HRV, as well as a technical review of the most common methods to measure it. In this work is presented a system that performs three measurements of HRV. An overview of methodologies developed to quantify HRV is presented; this technical review covers the most common time and frequency domain techniques, for short and long periods of time, with comments about clinical utility of these tests.
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Ohiagu, Franklyn O., Paul C. Chikezie, and Chinwendu M. Chikezie. "Pathophysiology of diabetes mellitus complications: Metabolic events and control." Biomedical Research and Therapy 8, no. 3 (2021): 4243–57. http://dx.doi.org/10.15419/bmrat.v8i3.663.
Full textAbstract:
Background: Diabetes mellitus (DM) is a metabolic disorder that is characterized by hyperglycemia and glucose intolerance, which is associated with impaired insulin secretion and peripheral sensitivity and eventual b-cell dysfunction. This review summarized the major metabolic pathways leading to both microvascular and macrovascular complications in DM, with a view of highlighting the enzymes involved and the possible inhibition of the enzymes facilitating these processes as a measure of diabetic control.
 Methods: Data used in writing this review were sourced online from scientific search engines such as Google Scholar, Scopus, EMBASE, PubMed, ResearchGate, Mendeley, Medline, and SpringerLink, using keywords such as 'diabetic complications', 'hyperglycemia-induced diabetic mechanisms', 'diabetic enzymes' and 'diabetic enzyme inhibitors'. A total number of 109 references published online between 1990 and 2020 were generated and cited in this review.
 Results: The most scourging and dilapidating effects of DM as well as associated vascular complications are classified into four categories viz.: nephropathy, retinopathy, neuropathy and cardiovascular disease. Hyperglycemia, which is associated with uncontrolled DM, elicits abnormal metabolism such that the enzymes involved in metabolic events leading to diabetic complications are expressed and amplified. The disorders associated with DM are linked to various metabolic pathways facilitated by enzyme activities of the polyol pathway, hexosamine biosynthetic pathway, glucose autoxidation as well as increased synthesis of advanced glycation end-products (AGEs), hexokinase-2 driven glycolytic overload, increased activities of the cyclooxygenase (COX), lipoxygenase (LOX) and pyruvate kinase (PKC) enzymes. The inhibition of the enzymes involved in these pathways could serve to mitigate and arrest diabetic complications.
 Conclusion: Thus, suitable inhibitors for enzymes involved in DM metabolic events could serve as panaceas against DM complications, which will add to the growing list of new and more efficacious antidiabetic drugs.
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Yanitskaya, L. V., L. F. Osinskaya, and A. V. Redko. "The role of nicotinamide in the correction of renal function in diabetic nephropathy." Reports of Vinnytsia National Medical University 23, no. 2 (2019): 218–21. http://dx.doi.org/10.31393/reports-vnmedical-2019-23(2)-06.
Full textAbstract:
Hyperglycemia of diabetes mellitus leads to the activation of the polyol way of oxidation of glucose with the activation of the enzymes of aldose reductase and sorbitol dehydrogenase and of their coenzymes NADPH and NAD, which triggers the mechanism of formation of sorbitol. The consequences of these changes lead to microangiopathy of the tissues of the kidneys, which may be one of the pathogenetic mechanisms of diabetic nephropathy. In an accessible literature, the role of coenzymes of sorbitol pathway in the development of diabetic nephropathy is not sufficiently defined. The purpose of the study was to study the content of NAD and NADPH coenzymes, their correlation, and their role in the mechanism of kidney damage in diabetes mellitus and to predict the possible correction of these changes with the NAD-nicotinamide derivative. The study was conducted on a model of streptotrozectinic diabetes mellitus (single administration of streptozotocin in a dose of 60 mg per 1 kg of body weight). Four weeks after induction of diabetes, nicotinamide (100 mg per 1 kg body weight) was injected. The level of glucose was determined by the Accu-chek (Roshe Diagnostics, Switzerland) glucose meter. The content of NAD and NADH was determined in the non-protein extracts. The statistical analysis was carried out using the Microsoft Excel statistical analysis program. The difference between the indicators was considered statistically significant (p<0.05). The NAD level was reduced by 31%, the NAD/NADN ratio was 32%. The dependence of the ratio of NADP/NADPN in conditions of hyperglycemia of diabetes mellitus with clinical manifestations of diabetic nephropathy is determined. A decrease in the ratio of NADP/NADPN to 38% in the rat kidney in the cortical layer was detected. The introduction of nicotinamide normalized the reduced content of NAD diabetic rats. These results provide perspectives for further research in which nicotinamide can be used as a renal protector.
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S-L, Zhang, X. Chen, TJ Hsieh, et al. "Hyperglycemia induces insulin resistance on angiotensinogen gene expression in diabetic rat kidney proximal tubular cells." Journal of Endocrinology 172, no. 2 (2002): 333–44. http://dx.doi.org/10.1677/joe.0.1720333.
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Clinical and animal studies have shown that treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor antagonists slows the progression of nephropathy in diabetes, indicating that Ang II plays an important role in its development. We have reported previously that insulin inhibits the stimulatory effect of high glucose levels on angiotensinogen (ANG) gene expression in rat immortalized renal proximal tubular cells (IRPTCs) via the mitogen-activated protein kinase (p44/42 MAPK) signal transduction pathway. We hypothesize that the suppressive action of insulin on ANG gene expression might be attenuated in renal proximal tubular cells (RPTCs) of rats with established diabetes. Two groups of male adult Wistar rats were studied: controls and streptozotocin (STZ)-induced diabetic rats at 2, 4, 8 and 12 weeks post-STZ administration. Kidney proximal tubules were isolated and cultured in either normal glucose (i.e. 5 mM) or high glucose (i.e. 25 mM) medium to determine the inhibitory effect of insulin on ANG gene expression. Immunoreactive rat ANG (IR-rANG) in culture media and cellular ANG mRNA were measured by a specific radioimmunoassay and reverse transcription-polymerase chain reaction assay respectively. Activation of the p44/42 MAPK signal transduction pathway in rat RPTCs was evaluated by p44/42 MAPK phosphorylation employing a PhosphoPlus p44/42 MAPK antibody kit. Insulin (10(-7) M) inhibited the stimulatory effect of high glucose levels on IR-rANG secretion and ANG gene expression and increased p44/42 MAPK phosphorylation in normal rat RPTCs. In contrast, it failed to affect these parameters in diabetic rat RPTCs. In conclusion, our studies demonstrate that hyperglycaemia induces insulin resistance on ANG gene expression in diabetic rat RPTCs by altering the MAPK signal transduction pathway.
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Sudipta, Dutta. "Study of Microalbuminuria as a Nephropathic Marker in Patients Suffered from Type 2 Diabetes Mellitus and its Correlation with the Glycated Hemoglobin." International Journal of Toxicological and Pharmacological Research 12, no. 11 (2022): 60–68. https://doi.org/10.5281/zenodo.11421263.
Full textAbstract:
Diabetic nephropathy is the leading cause of end-stage renal failure in patients with Type 2 DM, and its prevalence is increasing annually worldwide. Compared to 20 years ago, the incidence of diabetic complications without diabetic nephropathy has decreased; however, is still the main complication in diabetes. Microalbuminuria is defined as levels of albumin ranging from 30 to 300 mg in a 24-hrs urine collection. Microalbuminuria was the strongest predictor of cardiovascular events in a high-risk population with underlying atherosclerosis. It was found to be stronger than other risk factors such as coronary artery disease and diabetes. Microalbuminuria does not directly cause cardiovascular events; it serves as a marker for identifying those who may be at increased risk. Microalbuminuria is caused by glomerular capillary injury and so may be a marker for diffuse endothelial dysfunction. Hence based on above findings the present study was planned for Assessment of Prevalence of Microalbuminuria as a Nephropathic Marker in Patients Suffered from Type 2 Diabetes Mellitus and its Correlation with the Glycated Hemoglobin. The present study was planned in Department of Biochemistry, Shri Ramkrishna institute of medical sciences and Sanaka Hospitals, Durgapur, West Bengal, India for 1 year . Total 40 cases were enrolled in the present study. The 20 cases were enrolled in Group A as cases of diabetes mellitus and 20 cases were enrolled in Group B as control cases for comparative study. The data generated from the present study concluded that estimating glycosylated hemoglobin as an indicator of glycaemic control and microalbuminuria in random urine sample for renal involvement in diabetic subjects provide a convenient method for early diagnosis and intervention. Hence the microalbuminuria is nephrotic market in cases diagnosed with the diabetes mellitus. Hyperglycemia is the major factor initiating the changes in the kidney. The tissue damage caused by hyperglycemia can be attributed to the hemodynamic factor, glycosylation of tissue proteins and increase activity of the polyol pathway.
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Xie, Ping, Lin Sun, Peter J. Oates, Satish K. Srivastava, and Yashpal S. Kanwar. "Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis." American Journal of Physiology-Renal Physiology 298, no. 6 (2010): F1393—F1404. http://dx.doi.org/10.1152/ajprenal.00137.2010.
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Renal-specific oxido-reductase/ myoinositol oxygenase (RSOR/MIOX) is expressed in renal tubules. It catabolizes myo-inositol and its expression is increased in diabetic mice and in LLC-PK1 cells under high-glucose ambience. Aldose reductase (AR) is another aldo-keto reducase that is expressed in renal tubules. It regulates the polyol pathway and plays an important role in glucose metabolism, osmolyte regulation, and ECM pathobiology via the generation of advanced glycation end products, reactive oxygen species, and activation of transforming growth factor (TGF)-β. In view of the similarities between AR and RSOR/MIOX, the pathobiology of RSOR/MIOX and some of the cellular pathways affected by its overexpression were investigated. An increased expression of fibronectin was noted by transfection of LLC-PK1 cells with pcDNA3.1-RSOR/MIOX. Similar changes were observed in LLC-PK1 cells under high-glucose ambience, and they were notably lessened by RSOR/MIOX-small interfering (si) RNA treatment. The changes in tubulointerstitial fibronectin expression were also observed in the kidneys of db/db mice having high levels of RSOR. The pcDNA3.1-RSOR/MIOX transfectants had an increased NADH/NAD+ ratio, PKC and TGF-β activity, Raf1:Ras association, and p-ERK phosphorylation. These changes were significantly reduced by the inhibitors of PKC, aldose reductase, Ras farnesylation, and MEK1. Similar increases in various the above-noted parameters were observed under high-glucose ambience. Such changes were partially reversed with RSOR-siRNA treatment. Expression of E-cadherin and vimentin paralleled in cells overexpressing RSOR/MIOX or subjected to high-glucose ambience. These studies suggest that RSOR/MIOX modulates various downstream pathways affected by high-glucose ambience, and conceivably it plays a role in the pathobiology of tubulointerstitium in diabetic nephropathy.
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Addissouky, Tamer A. "Emerging Therapeutics Targeting Cellular Stress Pathways to Mitigate End-Organ Damage in Type 1 Diabetes." Avicenna Journal of Medical Biochemistry 12, no. 1 (2024): 39–46. http://dx.doi.org/10.34172/ajmb.2527.
Full textAbstract:
Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency and impaired glucose regulation. While daily insulin therapy is life-saving, many patients struggle to achieve optimal glycemic control, leading to microvascular complications affecting various organs, including the kidneys and the liver. This review aims to summarize the current state of knowledge regarding the pathogenesis of hepatic and renal complications in T1D, highlight recent advances in potential therapeutic targets, and provide evidence-based recommendations for mitigating end-organ damage. Chronic hyperglycemia drives diabetic complications through several interrelated mechanisms, including increased polyol pathway flux, advanced glycation end-product (AGE) formation, protein kinase C activation, and mitochondrial reactive oxygen species overproduction. In the liver, these processes contribute to non-alcoholic fatty liver disease, with up to 50% of T1D patients developing hepatic steatosis. Diabetic nephropathy, affecting 25%–40% of long-term T1D patients, is characterized by glomerular basement membrane thickening, mesangial expansion, and tubulointerstitial fibrosis. Recent innovations in T1D management include genomics and precision medicine approaches, gut microbiome modulation, nanomedicine, and artificial intelligence-driven glucose monitoring systems. Emerging immunotherapies aim to fundamentally modify the autoimmune response in T1D. Mitigating T1D complications requires intensive glycemic control, targeted pharmacotherapy, and lifestyle modifications. Emerging therapies and precision medicine approaches offer promising avenues. Ongoing research into molecular mechanisms remains crucial for developing novel interventions and improving long-term outcomes in T1D patients.
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Choudhary, Shalki, Vinni Kalra, Manoj Kumar, Ashok Kumar Tiwary, Jatin Sood, and Om Silakari. "Bio-Inspired Strategies against Diabetes and Associated Complications: A Review." Recent Patents on Drug Delivery & Formulation 13, no. 4 (2020): 273–82. http://dx.doi.org/10.2174/1872211314666191224120145.
Full textAbstract:
Bio-molecules are the most important target to be considered while designing any drug delivery system. The logic lies in using such bio-sensing or bio-mimicking systems in their formulations that can mimic the active site of those receptors to which the drug is going to bind. Polymers mimicking the active site of target enzymes are regarded as bio-inspired polymers and can be used to ameliorate many diseased conditions. Nowadays, this strategy is also being adopted against diabetes and its complications. Under hyperglycemic conditions, many pathways get activated which are responsible for the progression of diabetes-associated secondary complications viz. retinopathy, neuropathy, and nephropathy. The enzymes involved in the progression of these complications can be mimicked for their effective management. For an instance, Aldose Reductase (ALR2), a rate-limiting enzyme of the polyol pathway (downstream pathway) which gets over-activated under hyperglycemic condition is reported to be mimicked by using polymers which are having same functionalities in their structure. This review aims at critically appraising reports in which target mimicking bio-inspired formulations have been envisaged against diabetes and its complications. The information summarized in this review will provide an idea about the bio-sensing approaches utilized to manage blood glucose level and the utility of bio-inspired polymers for the management of diabetic complications (DC). Such type of information may be beneficial to pharmaceutical companies and academia for better development of targeted drug delivery systems with sustained-release property against these diseased conditions.
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Conklin, Daniel J., Petra Haberzettl, Kenneth G. MacKinlay, et al. "Aldose Reductase (AR) Mediates and Perivascular Adipose Tissue (PVAT) Modulates Endothelial Dysfunction of Short-Term High-Fat Diet Feeding in Mice." Metabolites 13, no. 12 (2023): 1172. http://dx.doi.org/10.3390/metabo13121172.
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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.
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Shah, Vallabh O., Marina Scavini, Jovanka Nikolic, et al. "Z−2 Microsatellite Allele Is Linked to Increased Expression of the Aldose Reductase Gene in Diabetic Nephropathy1." Journal of Clinical Endocrinology & Metabolism 83, no. 8 (1998): 2886–91. http://dx.doi.org/10.1210/jcem.83.8.5028.
Full textAbstract:
abstract Epidemiological studies support the hypothesis that genetic factors modulate the risk for diabetic nephropathy (DN). Aldose reductase (ALDR1), the rate-limiting enzyme in the polyol pathway, is a potential candidate gene. The present study explores the hypothesis that polymorphisms of the (A-C)n dinucleotide repeat sequence, located 2.1 kb upstream of the transcription start site, modulate ALDR1 gene expression and the risk for DN. We conducted studies at two different institutions, the University of New Mexico Health Sciences Center (UNMHSC), and the Istituto Scientifico H San Raffaele (HSR). There were four groups of volunteers at UNMHSC: group I, normal subjects; group II, patients with insulin-dependent diabetes mellitus (IDDM) without DN; group III, IDDM with DN; and group IV, nondiabetics with kidney disease. At HSR we studied volunteers in groups I, II, and III. ALDR1 genotype was assessed by PCR and fluorescent sequencing of the (A-C)n repeat locus, and ALDR1 messenger ribonucleic acid (mRNA) was measured by ribonuclease protection assay in peripheral blood mononuclear cells. At UNMHSC we identified 10 alleles ranging from Z−10 to Z+8. The prevalence of the Z−2 allele among IDDM patients was increased in those with DN. Sixty percent of group III and 22% of group II were homozygous for Z−2. Moreover, 90% and 67% of groups III and II, respectively, had 1 or more copy of Z−2. In contrast, among nondiabetics, 19% of group IV and 3% of group I were homozygous for Z−2, and 69% and 32%, respectively, had 1 copy or more of Z−2. Among diabetics, homozygosity for the Z−2 allele was associated with renal disease [odds ratio (OR), 5.25; 95% confidence interval, 1.71–17.98; P = 0.005]. ALDR1 mRNA levels were higher in patients with DN (group III; 0.113 ± 0.050) than in group I (0.068 ± 0.025), group II (0.042 ± 0.020), or group IV (0.015 ± 0.011; P &lt; 0.01). Among diabetics, ALDR1 mRNA levels were higher in Z−2 homozygotes (0.098 ± 0.06) and Z−2 heterozygotes (0.080 ± 0.04) than in patients with no Z−2 allele (0.043 ± 0.02; P &lt; 0.05). In contrast, among nondiabetics, ALDR1 mRNA levels in Z−2 homozygotes (0.034 ± 0.04) and Z−2 heterozygotes (0.038 ± 0.03) were similar to levels in patients without a Z−2 allele (0.047 ± 0.03; P = NS). At HSR we identified eight alleles ranging from Z−12 to Z+2. The prevalence of the Z−2 allele was higher in group III than in group II. In group III, 43% of the patients were homozygous for Z−2, and 81% had one copy or more of the Z−2 allele. In contrast, in group II, 4% were homozygous for Z−2, and 36% had one copy or more of the Z−2 allele. IDDM patients homozygous for Z−2 had an increased risk for DN compared with those lacking the Z−2 allele (OR, 18; 95% confidence interval, 2–159). IDDM patients who had one copy or more of Z−2 had increased risk (OR, 7.5; 95% confidence interval, 1.9–29.4) for DN compared with those without the Z−2 allele. These results support our hypothesis that environmental-genetic interactions modulate the risk for DN. Specifically, the Z−2 allele, in the presence of diabetes and/or hyperglycemia, is associated with increased ALDR1 expression. This interaction may explain the observed association between the Z−2 allele and DN.
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Barletto Sousa Barros, Jéssica, Rodrigo da Silva Santos, and Angela Adamski da Silva Reis. "Implication of the MAPK Signalling Pathway in the Pathogenesis of Diabetic Nephropathy." EMJ Diabetes, November 5, 2019, 107–14. http://dx.doi.org/10.33590/emjdiabet/10311665.
Full textAbstract:
Diabetes has become an emerging public health problem because of its serious complications, and high mortality and morbidity rates. Among the most common microvascular complications of diabetes is diabetic nephropathy (DN), which is a major cause of development of end-stage renal disease worldwide. The aetiopathogenesis of DN is not completely elucidated; however, studies have shown that the components of the MAPK signalling pathway play an essential role in the development and progression of the disease. The MAPK family is mainly composed of three subgroups: extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases (JNK) 1–3, and p38 MAPK, all of which are related to several cellular functions, such as cell death, differentiation, proliferation, motility, survival, stress response, and cell growth. In diabetic kidney disease, the MAPK pathway can be activated by processes resulting from hyperglycaemia (polyol pathway products, oxidative stress, and accumulation of advanced glycosylation end-products) and by angiotensin II, and it is related to several renal pathological processes. This review aims to summarise the role of the MAPK signalling pathway in diabetic nephropathy, as well as to link the biological aspects that contribute to clarify the pathological process behind the disease.
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Grey Venyo, Anthony Kodzo. "Diabetes Mellitus: A Review and Update." Journal of Ophthalmology Research Reviews & Reports, August 31, 2023, 1–24. http://dx.doi.org/10.47363/jorrr/2023(4)144.
Full textAbstract:
Diabetes mellitus is a group of metabolic diseases which are typified by the development of hyperglycaemia which do emanate from defects in insulin secretion, insulin action, or both. The chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Various types of diabetes mellitus exist which have been discussed in the main part of this article. Many pathogenic processes are involved in the development of diabetes mellitus. These pathogenic processes range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities which result in resistance to insulin action. The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes is deficient action of insulin on target tissues. Deficient insulin action ensues inadequate insulin secretion and / or diminished tissue responses to insulin at one or more points within the complex pathways of hormone action. Impairment of insulin secretion and defects in insulin action frequently coexist in the same patient, and it is often unclear which abnormality, if either alone, is the primary cause of the hyperglycaemia. The manifestations of marked hyperglycaemia do include: polyuria, polydipsia, weight loss, sometimes with polyphagia, and blurred vision. Impairment of growth and susceptibility to certain infections may also ensue chronic hyperglycaemia. Acute, life-threatening consequences of diabetes mellitus include: hyperglycaemia with ketoacidosis or the nonketotic hyperosmolar syndrome. Long-term complications of diabetes mellitus do include: diabetic retinopathy with potential loss of vision; diabetic nephropathy which leads to kidney (renal) failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints; as well as autonomic neuropathy which cause gastrointestinal, genitourinary, as well as cardiovascular symptoms and sexual dysfunction. Glycation of tissue proteins and other macromolecules and excess production of polyol compounds from glucose are among the mechanisms that had been postulated to produce tissue damage from chronic hyperglycaemia. Patients who have diabetes mellitus do have an increased incidence of atherosclerotic cardiovascular, peripheral vascular, and cerebrovascular disease. Hypertension, abnormalities of lipoprotein metabolism, and periodontal disease are often found in people who have diabetes mellitus. The emotional and social impact of diabetes mellitus as well as the demands of treatment of diabetes and its complications could cause significant psychosocial dysfunction in patients who have diabetes mellitus as well as their families. Even though there are many types of diabetes mellitus, the vast majority of cases of diabetes mellitus do fall into two broad etiopathogenetic categories which have been extensively discussed in the ensuing article below that has been divided into (a) Overview and (b) miscellaneous narrations. In one category of diabetes mellitus type 1 diabetes mellitus, the cause is an absolute deficiency of insulin secretion. Individuals at increased risk of developing this type of diabetes could often be identified by serological evidence of an autoimmune pathological process that occur within the pancreatic islets and by genetic markers. In the other type of diabetes mellitus, which is the much more prevalent category that is referred to as type 2 diabetes mellitus, the cause of the disease is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. In the latter category, a degree of hyperglycaemia sufficient to cause pathological and functional changes in various target tissues, but without clinical symptoms, could be present for a long period of time before diabetes mellitus is diagnosed. During this asymptomatic period, it is possible to demonstrate an abnormality in carbohydrate metabolism by measurement of plasma glucose in the fasting state or after a challenge with an oral glucose load. Considering that diabetes mellitus is common as well as the symptoms of diabetes mellitus are non-specific symptoms that may simulate diabetes mellitus, a number of individuals who are afflicted by diabetes mellitus do not know they have diabetes mellitus, there is need for a global educational program on the manifestations and approach that is needed for early diagnosis of the disease so that all clinicians and the entire global population would have a high index of suspicion of the disease. There also a global life style education including regular exercise that would delay onset of or reduce the severity of type 2 diabetes and to improve the quality of life of patients who have diabetes mellitus. It is important to dedicate time to read the article carefully which contains documentations related to the World Health Organization’s global effort to reduce the incidence and severity of diabetes mellitus and all individuals globally should follow carefully recommendations of the World Health organization as well as recommendations of other organizations in the world that have devoted their time to health education on diabetes mellitus. and a number of people
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Mathebula, Solani D. "Polyol pathway: A possible mechanism of diabetes complications in the eye." African Vision and Eye Health 74, no. 1 (2015). http://dx.doi.org/10.4102/aveh.v74i1.13.
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In complex diseases such as diabetes mellitus, the causative agents include various serum factors such as glucose, aldose reductase, oxygen-free radicals, advanced glycation end products, protein kinase-C and growth factors. The polyol pathway is a pathway of glucose metabolism and is regarded as an important element in the pathogenesis of refractive changes, cataract formation and diabetic retinopathy in individuals with diabetes mellitus. The focus of this review is on the role of the polyol pathway in the pathogenesis of diabetic complications in the eye. The first enzyme (aldose reductase) in the polyol pathway reduces glucose to sorbitol. The second enzyme (sorbitol dehydrogenase) converts sorbitol to fructose. The accumulation of sorbitol and fructose in the crystalline lens and retina leads to the generation of oxidative stress. Oxidative stress is the imbalance between levels of reactive oxygen species and the antioxidant defence in a biological system, and it results in tissue damage. How hyperglycaemia leads to oxidative stress is not clear but could be through a combination of increased levels of reactive oxygen species and decreased capacity of the cellular antioxidant system. Oxidative stress causes the development of diabetic complications that are seen clinically.
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HRNKOVÁ, Jana, Rudolf DUPÁK, and Marcela CAPCAROVÁ. "THE TOXIC EFFECT OF HYPERGLYCAEMIA IN THE PATHOGENESIS OF SELECTED CHRONIC COMPLICATIONS OF DIABETES MELLITUS: A MINI-REVIEW." Slovak Journal of Animal Science 55, no. 1–4 (2022). http://dx.doi.org/10.36547/sjas.796.
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Diabetes mellitus is a group of metabolic diseases that, due to the long-term pathological effect of hyperglycaemia on tissues, lead to the development of typical chronic organ complications. Chronic hyperglycaemia leads to increased activity of the polyol pathway with subsequent accumulation of sorbitol and fructose, increased formation and accumulation of end products of advanced glycation, alteration of protein kinase C activity, excessive formation of reactive oxygen species and associated high level of oxidative stress. One of the most feared complications of diabetes mellitus is vision impairment and blindness. In this review, we address the most important metabolic pathways leading to the development of diabetic retinopathy and diabetic cataract, the ocular complications of diabetes with the greatest risk of vision loss.
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Tiwari, Ruchi, Pranay Wal, Priya Singh, Gaurav Tiwari, and Awani Rai. "A Review on Mechanistic and pharmacological findings of Diabetic Peripheral Neuropathy including Pharmacotherapy." Current Diabetes Reviews 16 (September 14, 2020). http://dx.doi.org/10.2174/1573399816666200914141558.
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Background: Chronic hyperglycaemia and related complications involving peripheral nerves in diabetes are one of the most severe microvascular complications with an average prevalence of 50–60%. Diabetic neuropathy is among the vascular disorders of diabetes, the most debilitating and crippled, lethal condition impacting patients’s quality of life. Methods: In present review article, several hypothesis associated with pathogenesis of Diabetic Peripheral Neuropathy (DPN) have been introduced, out of which metabolic pathway associated with polyol pathway, oxidative stress, production of reactive oxygen species (ROS) amplified under chronic hyperglycemic conditions and activation of transcription factor Nuclear factor-κB (NF-κB). The review article also possesses pathogenetic and pharmacologic treatments along with other treatments including acupressure, lidocaine and capsaicin for DPN. Conclusion: It may be concluded that we can combat the pathogenesis of DPN with different suggested treatments.
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Efiong, Esienanwan Esien, Kathrin Maedler, Emmanuel Effa, et al. "Decoding diabetic kidney disease: a comprehensive review of interconnected pathways, molecular mediators, and therapeutic insights." Diabetology & Metabolic Syndrome 17, no. 1 (2025). https://doi.org/10.1186/s13098-025-01726-4.
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Abstract Background Diabetic kidney disease (DKD) is a chronic kidney condition that arises from prolonged hyperglycaemia that can progress to kidney failure, severe morbidity, and mortality if left untreated. It is the major cause of chronic kidney disease among people who have diabetes, accounting for a significant percentage of patients with end-stage kidney disease who require kidney replacement therapy. Main body In DKD, numerous dysbalanced metabolic, haemodynamic, inflammatory signalling pathways, and molecular mediators interconnect, creating a feedback loop that promotes general kidney damage. Hyperglycaemia is the primary trigger for DKD and leads gradually to oxidative stress, inflammation, extracellular matrix deposition and fibrosis, glomerular hypertension, and intrarenal hypoxia. Key interconnected metabolic pathways are the hyperglycaemia-mediated polyol, hexosamine, protein kinase C, and advanced glycation end-products pathway hyperactivity. Concurrently, hyperglycaemia-induced renin–angiotensin–aldosterone system stimulation, alters the kidney intraglomerular haemodynamic leading to inflammation through Toll-like receptors, Janus kinase/signal transducer and activator of transcription, and nuclear factor-kappa B, transforming growth factor-beta-mediated excessive extracellular matrix accumulation and fibrosis. The resulting death signals trigger apoptosis and autophagy through Hippo, Notch, and Wnt/β-catenin pathway activation and microRNA dysregulation. These signals synergistically remodel the kidneys culminating in intrarenal hypoxia, podocyte dysfunction, hyperfiltration, epithelial-mesenchymal transition, and loss of kidney function. The resulting renal failure further upregulates these death pathways and mediators, giving rise to a vicious cycle that further worsens DKD. Conclusion This review provides an overview of the primary molecular mediators and signalling pathways leading to DKD; their interconnectivity at the onset and during DKD progression, the central role of transforming growth factor-beta via different pathways, the Hippo pathway kidney-specific response to hyperglycaemia, and how all mediators and transduction signals result in a vicious circle that exacerbates renal failure. The review gives therapeutic sights to these pathways as druggable targets for DKD management. Understanding these molecular events underlying the pathogenesis of DKD can bridge basic research and clinical application, facilitating the development of innovative management strategies.
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Beniwal, Ankita, Jasmine Chaudhary Jain, and Akash Jain. "Lipids: A Major Culprit in Diabetic Nephropathy." Current Diabetes Reviews 20 (November 24, 2023). http://dx.doi.org/10.2174/0115733998259273231101052549.
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Abstract: The pathophysiology of diabetic nephropathy (DN) is too complex and involves a variety of pathways and mediators. Hyperglycaemia and dyslipidemia are identified as major risk factors for diabetic nephropathy. Various studies revealed the fact that dyslipidemia is a major contributor to the process of diabetic nephropathy. Dyslipidemia refers to abnormal lipid levels. Lipids like LDL, free fatty acids, abnormal lipoproteins, ceramides, etc., are unsafe for kidneys. They target proximal tubular epithelial cells, podocytes, and tubulointerstitial tissues through biochemical changes, especially by enhancing the release of reactive oxygen species (ROS) and lipid peroxidation, endorsing tissue inflammation and mitochondrial damage, which give rise to nephropathy. Major lipid targets identified are SREBP1, LXR, FXR PPAR, CD-36, PKc, AGE/RAGE pathway, and ferroptosis. The drug acting on these targets has shown improvement in DN patients. Various preclinical and clinical studies support the fact that hyperlipidemic agents are promising targets for DN. Therefore, in conjunction with other standard therapies, drugs acting on dyslipidemia can be added as a part of the regimen in order to prevent the incidence of ESRD and CVD.
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Gupta, Jeetendra Kumar. "The role of aldose reductase in polyol pathway: An emerging pharmacological target in diabetic complications and associated morbidities." Current Pharmaceutical Biotechnology 25 (August 30, 2023). http://dx.doi.org/10.2174/1389201025666230830125147.
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Abstract: The expression of aldose reductase leads to a variety of biological and pathological effects. It is a multifunctional enzyme which has a tendency to reduce aldehydes to the corresponding sugar alcohol. In diabetic conditions, the aldose reductase enzyme converts glucose into sorbitol using nicotinamide adenine dinucleotide phosphate as a cofactor. It is a key enzyme in polyol pathway which is a surrogate course of glucose metabolism. The polyol pathway has a significant impact on the aetiology of complications in individuals with end-stage diabetes. The exorbitant level of sorbitol leads to the accumulation of intracellular reactive oxygen species in diabetic heart, neurons, kidneys, eyes and other vasculatures, leading to many complications and pathogenesis. Recently, the pathophysiological role of aldose reductase has been explored with multifarious perspectives. Research on aldose reductase suggest that besides implying in diabetic complications, the enzyme also turns down the lipid-derived aldehydes as well as their glutathione conjugates. Although aldose reductase has certain lucrative role in detoxification of toxic lipid aldehydes, its overexpression leads to intracellular accumulation of sorbitol which is involved in secondary diabetic complications, such as neuropathy, cataractogenesis, nephropathy, retinopathy and cardiovascular pathogenesis. Osmotic upset and oxidative stress are produced by aldose reductase via the polyol pathway. The inhibition of aldose reductase alters the activation of transcription factors like NF-ƙB. Moreover, in many preclinical studies, aldose reductase inhibitors have been observed to reduce inflammation-related impediments, such as asthma, sepsis and colon cancer, in diabetic subjects. Targeting aldose reductase can bestow a novel cognizance for this primordial enzyme as an ingenious strategy to prevent diabetic complications and associated morbidities. In this review article, the significance of aldose reductase is briefly discussed along with their prospective applications in other afflictions.
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Jeffrey, Sarah, Punitha Isaac Samraj, and Behin Sundara Raj. "The role of alpha-lipoic acid supplementation in the prevention of diabetes complications: A comprehensive review of clinical trials." Current Diabetes Reviews 17 (January 18, 2021). http://dx.doi.org/10.2174/1573399817666210118145550.
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: Alpha-lipoic acid (ALA) is a substantial antioxidant in the prevention of diabetes and diabetes complications. It can regenerate other antioxidants like vitamin E, vitamin C, Coenzyme Q10 and glutathione and is often known as a universal antioxidant. Antioxidants play a role in diabetes treatment due to hyperglycemia-induced stimulation of the polyol pathway and formation of advanced glycation end products (AGE) and reactive oxygen species (ROS). Clinical trials examining alpha-lipoic acid supplementation on diabetic neuropathy, nephropathy, cardiomyopathy and erectile dysfunction display positive results, particularly in pain amelioration in neuropathy, asymmetric dimethylarginine reductions in nephropathy and improved oscillatory potential and contrast sensitivity in retinopathy. In diabetic cardiomyopathy (DCM), ALA offers protection through inhibition of NF-kB activation, reduction of fas-ligand and decrease in matrix metalloproteinase-2. This comprehensive review summarises and provides an understanding of the importance of alpha-lipoic acid supplementation to prevent diabetes complications.
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Shen, Huajuan, and Wei Wang. "Effect of glutathione liposomes on diabetic nephropathy based on oxidative stress and polyol pathway mechanism." Journal of Liposome Research, June 22, 2020, 1–9. http://dx.doi.org/10.1080/08982104.2020.1780607.
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Bhrigu, Bhanupriya, Shikha Sharma, Nitin Kumar, and Bimal Krishna Banik. "Assessment for Diabetic Neuropathy: Treatment and Neurobiological Perspective." Current Diabetes Reviews 20 (May 24, 2024). http://dx.doi.org/10.2174/0115733998290606240521113832.
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Abstract:: Diabetic neuropathy, also known as diabetic peripheral sensorimotor neuropathy (DPN), is a consequential complexity of diabetes, alongside diabetic nephropathy, diabetic cardiomyopathy, and diabetic retinopathy. It is characterized by signs and symptoms of peripheral nerve damage in diabetes patients after ruling out other causes. Approximately 20% of people with diabetes are affected by this painful and severe condition. The development of diabetic neuropathy is influenced by factors such as impaired blood flow to the peripheral nerves and metabolic issues, including increased polyol pathway activation, myo-inositol loss, and nonenzymatic glycation. The present review article provides a brief overview of the pathological changes in diabetic neuropathy and the mechanisms and types of DPN. Various diagnostic tests and biomarkers are available to assess nerve damage and its severity. Pharmacotherapy for neuropathic pain in diabetic neuropathy is complex. This review will explore current treatment options and potential future developments to improve the quality of life for patients suffering from diabetic neuropathy.
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Taha, Naglaa A., Aida A. Hussein, Heba N. Gad El-Hak, and Nahla S. El-Shenawy. "A mini-review of nanoparticle therapeutics targeting oxidative stress and inflammation in diabetes." Journal of Basic and Applied Zoology 86, no. 1 (2025). https://doi.org/10.1186/s41936-025-00449-2.
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Abstract Background Diabetes is intricately linked to oxidative stress and inflammation, primarily driven by elevated blood glucose levels that lead to excessive production of reactive oxygen species (ROS). The buildup of ROS surpasses the body's antioxidant defenses, leading to damage of proteins, lipids, and DNA, which in turn accelerates the development of diabetic complications. Key processes such as glucose auto-oxidation, activation of the polyol pathway, and the formation of advanced glycation end products (AGEs) significantly amplify the production of ROS. Mitochondrial dysfunction, particularly with aging, compounds the issue by decreasing ATP production while increasing ROS generation. Main text The oxidative stress that results hampers beta-cell function, decreases insulin production, and contributes to insulin resistance. Additionally, ROS-induced inflammation and vascular damage contribute to complications like diabetic retinopathy, nephropathy, and cardiovascular diseases. Chronic hyperglycemia further aggravates inflammation through the release of pro-inflammatory cytokines. Metabolic pathways contribute to sustained ROS production and weakened antioxidant defenses, including the polyol pathway, protein kinase C (PKC) activation, and the hexosamine pathway. Nanoparticles (NPs) with anti-inflammatory and antioxidant capabilities, such as gold, silver, and cerium oxide NPs, hold the potential for managing diabetes-related inflammation and oxidative stress. Conclusions Curcumin and metal NPs can target macrophages and promote wound healing, while antioxidant and polymeric NPs enhance the efficacy of natural antioxidants. Combination therapies and multifunctional NPs offer a synergistic approach to mitigate diabetic complications by targeting inflammation, oxidative stress, and glucose metabolism, highlighting the potential of NPs in diabetes management.
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Jia, Miao, Lihua Lin, Kang Xun та ін. "Indoxyl sulfate aggravates podocyte damage through the TGF-β1/Smad/ROS signaling pathway". Kidney and Blood Pressure Research, 10 травня 2024. http://dx.doi.org/10.1159/000538858.
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Introduction: Hyperglycaemia induces the production of a large quantity of reactive oxygen species (ROS) and activates the transforming growth factor β1(TGF-β1)/Smad signalling pathway, which is the main initiating factor in the formation of diabetic nephropathy. Indoxyl sulfate (IS) is a protein-binding gut-derived uraemic toxin that localizes to podocytes, induces oxidative stress and inflames podocytes. The involvement of podocyte damage in diabetic nephropathy through the TGF-β1/) signalling pathway is still unclear. Methods: In this study, we cultured differentiated rat podocytes in vitro and measured the expression levels of nephrin, synaptopodin, CD2AP, SRGAP2a and α-SMA by quantitative real-time PCR (qRT‒PCR) and western blotting after siRNA-mediated TGF-β1 silencing, TGF-β1 overexpression and the presence of the ROS inhibitor acetylcysteine. We detected the expression levels of nephrin, synaptopodin, CD2AP, SRGAP2a, SRGAP2a in the Smad2/3, phosphorylated-Smad2/3 (p-Smad2/3), Smad7, NADPH oxidase 4 (NOX4), and ROS levels under high glucose (HG) and IS conditions. Results: The results indicated that nephrin, synaptopodin, CD2AP and SRGAP2a expressions were significantly upregulated and α-SMA expression was significantly downregulated in the presence of HG under siRNA-mediated TGF-β1 silencing or after the addition of acetylcysteine. However, in the presence of HG, the expressions of nephrin, synaptopodin, CD2AP and SRGAP2a were significantly downregulated, and the expression of α-SMA was significantly upregulated with the overexpression of TGF-β1. IS supplementation under HG conditions further significantly reduced the expressions of nephrin, synaptopodin, CD2AP and SRGAP2a; altered the expressions of Smad2/3, p-Smad2/3, Smad7 and NOX4; and increased ROS production in podocytes. Conclusions: This study suggests that IS may modulate the expression of nephrin, synaptopodin, CD2AP and SRGAP2a by regulating the ROS and TGF-β1/Smad signalling pathways, providing new theoretical support for the treatment of diabetic nephropathy.