The Mechanisms of Inhibition of Advanced Glycation End Products Formation Through Polyphenols in Hyperglycemic Condition

32 Reviews The Mechanisms of Inhibition of Advanced Glycation End Products Formation through Polyphenols in Hyperglycemic Condition Authors Shahpour Khangholi1, Fadzilah Adibah Abdul Majid1, 2, Najat Jabbar Ahmed Berwary3, Farediah Ahmad4, Ramlan Bin Abd Aziz 2 Affiliations 1 Tissue Culture Engineering Laboratory, Universiti Teknologi Malaysia (UTM), Malaysia 2 Institute of Bio-products Development, Universiti Teknologi Malaysia (UTM), Malaysia 3 College of Medicine, Hawler Medical University, Erbil, Iraq 4 Department of Biochemistry, Faculty of Sciences, Universiti Teknologi Malaysia (UTM), Malaysia Key words Abstract the action mechanisms of the components of l" AGEs ! polyphenols. l" diabetic complications Glycation, the non-enzymatic binding of glucose l" polyphenols to free amino groups of an amino acid, yields irre- l" antiglycation versible heterogeneous compounds known as ad- Abbreviations l" hyperglycemia ! l" antioxidant vanced glycation end products. Those products play a significant role in diabetic complications. ALEs: advanced lipoxidation end products In the present article we briefly discuss the con- AGEs: advanced glycation end products tribution of advanced glycation end products to AR: aldose reductase the pathogenesis of diabetic complications, such CML: carboxymethyllysine as atherosclerosis, diabetic retinopathy, nephrop- EGCG: epigallocatechin-3-gallate athy, neuropathy, and wound healing. Then we GLUT-4: glucose transporter type 4 mention the various mechanisms by which poly- GO: glyoxal phenols inhibit the formation of advanced glyca- LDL: low density lipoprotein tion end products. Finally, recent supporting MGO: methylglyoxal documents are presented to clarify the inhibitory MMPs: matrix metalloproteinases effects of polyphenols on the formation of ad- NADPH: nicotinamide adenine dinucleotide vanced glycation end products. Phytochemicals phosphate hydrogen apply several antiglycation mechanisms, includ- NFκB: nuclear factor kappa B ing glucose metabolism, amelioration of oxidative PPAR: peroxisome proliferator-activated stress, scavenging of dicarbonyl species, and up/ receptors down-regulation of gene expression. To utilize RAGE: receptor for AGEs received June 30, 2014 polyphenols in order to remedy diabetic compli- ROS: reactive oxygen species revised June 25, 2015 α α accepted August 20, 2015 cations, we must explore, examine and clarify TNF- : tumor necrosis factor- VCAM-1: vascular cell adhesion molecule 1 Bibliography DOI http://dx.doi.org/ This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 10.1055/s-0035-1558086 Published online November 9, Introduction Diabetes is a chronic disease accompanied by hy- 2015 ! perglycemia. Hyperglycemia accelerates the de- Planta Med 2016; 82: 32–45 For thousands of years, plants have been used in velopment of diabetic complications by several © Georg Thieme Verlag KG traditional systems of medicine to remedy differ- mechanisms, including increase in hexosamine Stuttgart · New York · ISSN 0032‑0943 ent kinds of disorders. Based on the records from pathway flux, increase in polyol pathway flux, ac- 1981–2002, around 40% of 877 new discovered tivation of protein kinase C isomers, and increase Correspondence chemical entities originated from nature [1]. Be- in AGEs formation. AGEs contribute to the patho- Assoc. Professor Fadzilah Adibah Abdul Majid cause of the biological advantages of nature origi- genesis of diabetes complications. Therefore inhi- Head of Tissue Culture nated drugs, scientists throughout the world have bition of their formation is considered as a thera- Engineering Laboratory tried to explore and introduce new prototype peutic approach for patients. Many studies have Faculty of Chemical Engineering Universiti Teknologi Malaysia drugs against diseases. Therefore a massive been conducted to examine the antiglycation ac- 81310 Johor Bahru, Johor amount of information is needed to determine tivity of phytochemicals. It has been established Malaysia biological activity, action mechanisms, and fate that phytochemicals exert their effects via several Phone: + 60177853273 Fax:+6075535556 of these new molecules in the body. mechanisms, which are mostly dependent on the [email protected] molecular structure of the compounds. Khangholi S et al. The Mechanisms of… Planta Med 2016; 82: 32–45 Reviews 33 Fig. 1 Protein glycation pathways leading to AGEs formation. Advanced Glycation End Product Formation glyoxal or methylglyoxal with free lysine groups of proteins gives ! rise to the formation of AGEs such as CML, carboxyethyllysine or Glycation (non-enzymatic glycosylation) is a chemical reaction in methylglyoxal lysine dimer [9]. which the carbonyl group of a reducing sugar binds to an amino group of long-lived proteins, lipids, or peptides in the absence of enzymatic control to finally produce AGEs [2]. AGEs are heteroge- Role of Advanced Glycation End Products in the neous compounds in the form of fluorescent cross-linking (e.g. Pathogenesis of Diabetic Complications pentosidine), non-fluorescent cross-linking (methylglyoxal-ly- ! This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. sine dimers) and non-fluorescent non-cross-linking (CML and AGEs contribute to the development and progression of diabetes pyrraline) [3]. In the initial stage of glycation, carbonyl groups of complications, including micro- or macroangiopathy. AGEs exert reducing sugars such as glucose, fructose, or trioses bind to free their damaging effects on cell functions through several mecha- amino groups of proteins in the absence of enzymatic control nisms such as production of free radicals, fragmentation of pro- [4]. The yields of this reaction are known as Schiff base inter- tein or lipid, altering enzyme activity, modifying immunogenic- mediates, which are unstable and reversible. In the second stage ity, oxidation of nucleic acids or lipids, carbonyl stress or interac- the compounds, after dehydration and rearrangement, convert to tion with AGEs receptors on the cell surface [10]. more stable Amadori products. Finally, after dehydration, oxida- The AGEs are capable of forming an AGE-receptor complex by tion and rearrangement, the Amadori products yield stable and binding to specific or non-specific receptors such as AGE‑R1 irreversible compounds known as AGEs (l" Fig. 1) [5,6]. More- (P60/OST-48 protein), AGE‑R2 (80 K‑H phosphoprotein), AGE‑R3 over, a variety of other pathways such as autoxidation of glucose, (galectin), and AGE-RAGE [11–13]. Among different receptors or ascorbate and lipid peroxidation, can also lead to AGE forma- RAGE as a multi-ligand receptor of the immunoglobulin super- tion. The yields of these pathways usually are dicarbonyl inter- family, plays a distinguished role in the onset of AGEs induced mediates, for example MGO, GO, 3-deoxyglucosone, glycolalde- metabolic disorders (l" Fig. 2). AGE-RAGE complex not only alters hyde, 1-deoxyglucosone [7] and free radicals [8]. Reaction of the structures and functions of proteins but also activates some Khangholi S et al. The Mechanisms of… Planta Med 2016; 82: 32–45 34 Reviews Fig. 2 Simplified mechanisms of the pathogenesis of AGEs in hyperglyce- and mitochondria ROS formation cause oxidative stress. Intercellular AGEs mia condition. RAGE comprises of three extracellular domains (V, C1, and are produced by glycation of the cytoplasmic proteins. All these events in- C2), a transmembrane domain (TMD) and cytoplasmic tail (CT). AGE-RAGE duce transcription factors and finally pro-inflammatory agents which lead to activate NADPH oxidase which produces ROS. Autoxidation of glucose (AOx) diabetic complications. intercellular signaling pathways such as those of protein kinase C sion of monocyte to endothelial cells. In the next stage, mono- or transcription factor NFκB, triggers NADPH-oxidase, chemo-at- cytes differentiate into intimal macrophages, which transform tractive and proinflammatory gene expression [14], VCAM-1, or into the foam cells by lipid uptake [24]. intercellular adhesion molecules-1 (ICAM-1) [15]. Diabetic retinopathy Atherosclerosis Retinopathy is the most common cause of blindness in diabetic Diabetes is recognized as a noticeable risk factor for the progress patients. In diabetic retinopathy, accumulation of AGEs promotes of atherosclerosis, which is a major contributor to morbidity and disorders such as thickening of the capillary basement mem- mortality in diabetic patients. Hyperglycemia result in higher ac- brane, enhancing of permeability of capillaries and vascular leak- cumulated amounts of AGEs in the blood vessels that induces age, apoptosis of pericytes [25], prevention of DNA synthesis of proliferation of smooth muscle cell, thickening of intima (due to retinal pericytes, and finally increasing of endothelial cell death plaque formation and its sedimentation), and rigidity and stiff- [26]. AGEs receptors are located on the surface of pericytes. Hy- ness of the vessels [16,17]. Foam cell formation is considered as perglycemia stimulates an excessive expression of RAGE on peri- a risk factor for atherosclerosis. AGEs contribute to foam cell for- cytes and endothelial cells which results in a deterioration of mation through several mechanisms such as enhancement of lip- pericytes. Loss of pericytes leads to vascular damage and clinical id and protein glycosylation [18], lipid uptake, increasing pro- expression of retinopathy [27,28]. Moreover, a high level of AGEs duction of ALEs, or

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