HDAC Inhibitors as Epigenetic Regulators

The presence of LMW-MAGE, with a mass to charge (m/z) ratio of 513.23, appearing at approx. (58.1% and 57.8%). In conclusion, newly developed immunoassay allows for AGE10 quantification. AGE10 elevation is usually associated with microangiopathy while its decrease accompanies stage 3 chronic kidney disease. Keywords:advanced glycation end-products, diabetes, microangiopathy, glomerular filtration == 1. Introduction == Biochemical pathways contributing to diabetes-related damage of organs and blood vessels are being intensively investigated and the relevance of protein glycation is well recognized now. Glycation is usually a physiological process involved in aging, which, however, accelerates substantially in metabolic disorders [1,2]. The important role of protein glycation in conditions associated with hyperglycemia has been emphasized for many years. Most of advanced glycation end-products (AGE) are formed during the nonenzymatic Maillard reaction [3], wherein, Schiff base is formed in the initial stages. Then, it is converted into Amadori product which, in a cascade of various reactions, ultimately leads to the AGE formation. Glycation occurs between the reducing sugars or low molecular mass aldehydes (e.g., -oxoaldehydes, hydroxyaldehydes) and the basic groups of proteins, lipids or nucleic acids, yielding compounds varying in structure and stability [4]. Long-lived proteins such as plasminogen activator inhibitor (PAI)-1, fibrinogen or albumin and extracellular matrix (ECM) proteins are particularly susceptible to glycation and subsequent formation of AGE [5,6]. In turn, glycation of proteins with short Oxypurinol half-lives leads to the formation of Amadori products such as HbA1c in case of hemoglobin. Glycation impairs protein function to varying degrees. Moreover, modified proteins become resistant to degradation and are targeted by immune cells inducing inflammation [7], which, unresolved, may lead to cancer [8]. The accumulation of AGE has been shown in adipose tissue, muscles, nerves or blood plasma [9,10,11,12,13]. Moreover, the AGE presence may disturb the nerve impulse conduction in muscles contributing to amyotrophic lateral sclerosis called Charcot disease [14]. Increased AGE accumulation in tissues, as well as glucose intolerance or abnormal glucose metabolism are significant risk factors for accelerated atherosclerosis and cardiovascular diseases [15]. Hyperglycemia can lead to dysfunction of contractile myocytes (diabetic cardiomyopathy), occurring most often in patients with type 1 diabetes [14,16]. AGEs may damage ryanodine receptor in myocytes altering calcium transfer from sarcoplasmic reticulum to mitochondria in the senescent myocardium [17]. The cardiovascular system diseases, especially coronary heart disease (CHD), are the leading cause of death in patients with type 2 diabetes [15]. The progressive glycation can also affect the central nervous system (CNS), damaging the brain and peripheral nerves and autonomic nervous system (ANS) Rabbit Polyclonal to HSP90B (phospho-Ser254) [18,19]. Kidneys are among organs particularly affected by AGE accumulation [20]. The loss of unfavorable charge of Oxypurinol the nephron filtration barrier accelerates the process, causing oxidative stress and upregulating expression of pro-inflammatory cytokines [20]. Animal studies have shown that AGE exacerbated diabetic nephropathy, which, in turn, contributed to the thickening and hardening of the glomerular basement membrane, fibrosis of tubular structures of renal mesangial cells, and increased the expression of TGF- and collagen IV [21]. Moreover, as a result of chronic hyperglycemia, the synthesis of angiotensin II increases, rising the blood pressure, aggravating inflammation and oxidative stress, and leading to proteinuria and, ultimately, glomerular fibrosis [22]. Recently, we have characterized a new synthetic glycation Oxypurinol end-product, MAGE, which is produced by the modification of proteins by melibiose. MAGE is a synthetic analogue of AGE epitope that presence has been detected in tissues from invertebrates, such as snails, and vertebrates, including fish, frog, chicken, pig, horse, rat, rabbit and human. MAGE creates isomers of fructosamine that contain an attached disaccharide, in which both carbohydrate moieties (i.e., galactose and glucose) are in a closed form, in contrast to fructosamine formed from glucose or fructose [23]. The exact structure of AGE epitope remains unraveled while that of MAGE is elaborated in Staniszewska et al. [24]. Importantly, autoantibodies against this epitope have been detected in serum samples from diabetic patients [24]. They.