The neoepitopes on methylglyoxal (MG) glycated LDL create autoimmune response; autoimmunity detection in T2DM patients with varying disease duration

Khan, Mohd Yasir; Alouffi, Sultan; Khan, Mohd Shahnawaz; Husain, Fohad Mabood; Akhter, Firoz; Ahmad, Saheem

doi:10.1016/j.cellimm.2020.104062

Cited by 19 publications

(27 citation statements)

References 41 publications

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“…The interaction of AGEs with RAGE sets off a cascade of events leading to the modulation of the gene expression and loss of vascular and tissue homeostasis, the processes that contribute to cardiovascular diseases [26] lung cancer [27], pancreatic cancer [28], hepatocellular carcinoma [29], and various other forms of cancer as well [30,31]. Hence, Since AGEs are implicated in type 2 diabetes mellitus as reported by us and others [32,33], there is a strong link between diabetes and cancer [34]. Diabetes is associated with increased risk for some cancers like the liver, pancreas, endometrium, colon, breast, and bladder.…”

Section: Discussionmentioning

confidence: 77%

Inhibitory Effect of Multimodal Nanoassemblies against Glycative and Oxidative Stress in Cancer and Glycation Animal Models

Khan

Waseem

Faisal

et al. 2021

BioMed Research International

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In recent years, there has been a progress in the study of glycation reaction which is one the possible reason for multiple metabolic disorders. Glycation is a nonenzymatic reaction between nucleic acids, lipids, and proteins resulting into the formation of early glycation products that may further lead to the accumulation of advanced glycation end products (AGEs). The precipitation of AGEs in various cells, tissues, and organs is one of the factors for the initiation and progression of various metabolic derangements including the cancer. The AGE interaction with its receptor “RAGE” activates the inflammatory pathway; yet, the downregulation of RAGE and its role in these pathways are not clear. We explore the effect of anticancer novel nanoassemblies on AGEs to determine its role in the regulation of the expression of RAGE, NFƙB, TNF-α, and IFN-γ. This paper is based on the in vivo and in vitro study in glycation and lung cancer model systems. Upon the treatment of nanoassemblies in both the model systems, we observed a protective effect of nanoassemblies over the inhibition of glycative and oxidative stress via mRNA expression analysis. The mRNA expression results corroborated with the reactive oxygen species (ROS), carboxy-methyl-lysine (CML), and fluorescence studies. In this study, we found that the presence of common factors for glycation and lung cancer is oxidative and glycative stress. This oxidation and glycation might be responsible for the initiation of inflammation which may further lead to uncontrolled growth of cells leading to cancer. This can be a strong association between lung cancer and glycation reaction. The intervention of the anticancer and antiglycation effects of multimodal nanoassemblies throughout the study promises a new pathway for cancer research.

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Section: Discussionmentioning

confidence: 77%

Inhibitory Effect of Multimodal Nanoassemblies against Glycative and Oxidative Stress in Cancer and Glycation Animal Models

Khan

Waseem

Faisal

et al. 2021

BioMed Research International

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“…The glycation of LDL increases LDL-AGEs with antigenic epitopes to induce autoantibody production that will lead to the accumulation AGE-IgG immune complexes [ 10 , 39 ]. The accelerated AGE-IgG-IC accumulation creates oxidative stress in the kidney of diabetic rat which may induce kidney lesion [ 22 , 39 , 63 , 64 ].…”

Section: Resultsmentioning

confidence: 99%

“…Glycation causes damage to LDL and other plasma proteins that might serve as a predictor for early detection of diabetes. Our previous study revealed that MG-modified glycated LDL might be a potential target for circulating autoantibodies against glycated LDL, which increases with the increase in duration of type 2 diabetes mellitus [ 10 ]. The autoantibodies that react with glycated LDL generates both intra- and extravascular immune complexes, which may further contribute to other immune factors involved in the destruction of β -cells of the pancreas [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Characterization of In Vitro LDL Glycation and Its Inhibition by Ellagic Acid (EA): An In Vivo Approach to Inhibit Diabetes in Experimental Animals

Ahmad

Alouffi

Khan

et al. 2022

BioMed Research International

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Hundreds of millions of people around the globe are afflicted by diabetes mellitus. The alteration in glucose fixation process might result into hyperglycaemia and could affect the circulating plasma proteins to undergo nonenzymatic glycation reaction. If it is unchecked, it may lead to diabetes with increase in advanced glycation end products (AGEs). Therefore, the present study was designed to inhibit the diabetes and glycation by using natural antioxidant “ellagic acid” (EA). In this study, we explored the antidiabetes and antiglycation potential of EA in both in vitro (EA at micromolar concentration) and in vivo systems. The EA concentrations of 10 and 20 mg kg-1B.W./day were administered orally for 25 days to alloxan-induced diabetic rats, a week after confirmation of stable diabetes in animals. Intriguingly, EA supplementation in diabetic rats reversed the increase in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) level. EA also showed an inhibitory role against glycation intermediates including dicarbonyls, as well as AGEs, investigated in a glycation mixture with in vitro and in vivo animal plasma samples. Additionally, EA treatment resulted in inhibition of lipid peroxidation-mediated malondialdehyde (MDA) and conjugated dienes (CD). Furthermore, EA exhibited an antioxidant property, increased the level of plasma glutathione (GSH), and also helped to decrease histological changes evaluated by histoimmunostaining of animal kidney tissues. The results from our investigation clearly indicates the antiglycative property of EA, suggesting EA as an adequate inhibitor of glycation and diabetes, which can be investigated further in preclinical settings for the treatment and management of diabetes-associated complications.

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“…Moreover, in the persistent hyperglycemic state, the concentration of dicarbonyls was significantly elevated [ 11 ]. Furthermore, exposure and generation of neoepitopes on glycated proteins render them highly immunogenic which leads to the production of autoantibodies [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Glycation of fibrinogen with MG results in structural modifications and exposure of neoepitopes that elicit immune responses in experimental animals [ 38 ]. Previous studies by our research group have revealed the presence of autoantibodies against d-ribose-glycated LDL, d-ribose-glycated hemoglobin (Hb), and MG-glycated LDL in type 2 diabetes mellitus (T2DM) and its associated secondary complications [ 39 – 44 ]. Therefore, we hypothesized that MG-mediated glycation of fibrinogen leads to the generation of autoantibodies (anti-MG-Fib-IgG) in a hyperglycemic state.…”

Section: Introductionmentioning

confidence: 99%

The Neoepitopes on Methylglyoxal‐ (MG‐) Glycated Fibrinogen Generate Autoimmune Response: Its Role in Diabetes, Atherosclerosis, and Diabetic Atherosclerosis Subjects

Rehman

Song

Faisal

et al. 2021

Oxidative Medicine and Cellular Longevity

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Objectives. In diabetes mellitus, hyperglycemia-mediated nonenzymatic glycosylation of fibrinogen protein plays a crucial role in the pathogenesis of micro- and macrovascular complications especially atherosclerosis via the generation of advanced glycation end products (AGEs). Methylglyoxal (MG) induces glycation of fibrinogen, resulting in structural alterations that lead to autoimmune response via the generation of neoepitopes on protein molecules. The present study was designed to probe the prevalence of autoantibodies against MG-glycated fibrinogen (MG-Fib) in type 2 diabetes mellitus (T2DM), atherosclerosis (ATH), and diabetic atherosclerosis (T2DM-ATH) patients. Design and Methods. The binding affinity of autoantibodies in patients’ sera (T2DM, n = 100 ; ATH, n = 100 ; and T2DM-ATH, n = 100 ) and isolated immunoglobulin G (IgG) against native fibrinogen (N-Fib) and MG-Fib to healthy subjects (HS, n = 50 ) was accessed by direct binding ELISA. The results of direct binding were further validated by competitive/inhibition ELISA. Moreover, AGE detection, ketoamines, protein carbonyls, hydroxymethylfurfural (HMF), thiobarbituric acid reactive substances (TBARS), and carboxymethyllysine (CML) concentrations in patients’ sera were also determined. Furthermore, free lysine and free arginine residues were also estimated. Results. The high binding affinity was observed in 54% of T2DM, 33% of ATH, and 65% of T2DM-ATH patients’ samples with respect to healthy subjects against MG-Fib antigen in comparison to N-Fib ( p < 0.05 to p < 0.0001 ). HS sera showed nonsignificant binding ( p > 0.05 ) with N-Fib and MG-Fib. Other biochemical parameters were also found to be significant ( p < 0.05 ) in the patient groups with respect to the HS group. Conclusions. These findings in the future might pave a way to authenticate fibrinogen as a biomarker for the early detection of diabetes-associated micro- and macrovascular complications.

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The neoepitopes on methylglyoxal (MG) glycated LDL create autoimmune response; autoimmunity detection in T2DM patients with varying disease duration

Cited by 19 publications

References 41 publications

Inhibitory Effect of Multimodal Nanoassemblies against Glycative and Oxidative Stress in Cancer and Glycation Animal Models

Inhibitory Effect of Multimodal Nanoassemblies against Glycative and Oxidative Stress in Cancer and Glycation Animal Models

Physicochemical Characterization of In Vitro LDL Glycation and Its Inhibition by Ellagic Acid (EA): An In Vivo Approach to Inhibit Diabetes in Experimental Animals

The Neoepitopes on Methylglyoxal‐ (MG‐) Glycated Fibrinogen Generate Autoimmune Response: Its Role in Diabetes, Atherosclerosis, and Diabetic Atherosclerosis Subjects

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