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Agmatine Prevents Oxidative-Nitrative Stress in Blood Leukocytes Under Open Life Sci. 2019; 14: 299–310 Research Article Ivanna Bila, Olha Dzydzan, Iryna Brodyak*, Natalia Sybirna Agmatine prevents oxidative-nitrative stress in blood leukocytes under streptozotocin-induced diabetes mellitus https://doi.org/10.1515/biol-2019-0033 Received January 14, 2019; accepted April 4, 2019 1 Introduction Abstract: Changes in cellular metabolism, development of Type 1 diabetes mellitus (DM) is characterized by a oxidative-nitrative stress and intensification of glycation progressive autoimmune destruction of pancreatic β-cells, and lipid peroxidation (LPO), are significant processes that leading to insulin deficiency and chronic hyperglycemia occur during diabetes mellitus (DM)-associated chronic [1]. Some pathways of glucose metabolism that are hyperglycemia. These processes contribute to deviations activated under conditions of hyperglycemia include in the structural organization and functional activity of the autooxidation of glucose and its intermediates to leukocytes. The development of oxidative-nitrative stress methylglyoxal, glyoxal and 3-deoxyglucosone, which in peripheral blood cells during DM can be prevented by cause non-enzymatic glycosylation of long-lived proteins; agmatine, an endogenous metabolite of L-arginine, which the hexosamine pathway producing uridine diphosphate- is a nitric oxide synthase (NOS) inhibitor, and possesses N-acetylglucosamine which contributes to the hypoglycemic properties. The administration of agmatine to glycosylation of serine and threonine residues; sorbitol animals with DM lead to the inhibition of both constitutive metabolism, which leads to free radical generation and and inducible NOS in leukocytes, which in turn decreased lower reduced glutathione (GSH) activity; and oxidative total nitrite/nitrate (NOx) levels. Additionally, we observed phosphorylation leading to mitochondria electron corresponding increases in reduced glutathione content transport chain intensification and the generation of •− and activity of antioxidant enzymes (SOD, CAT, GPx, GR), superoxide-anion (O2 ) radicals [2–6]. The inhibition of along with decreased levels of the thiobarbituric acid glycolysis leads to an accumulation of triose phosphates, reactive substance, advanced oxidation protein products which metabolize to carbonyl compounds that take part (AOPPs) and advanced glycosylation end-products (AGEs) in oxidative modification of proteins, lipids and DNA. as compared to the non-treated diabetic group. Our results Oxidized proteins activate proteolysis which enhance indicate that treatment of diabetic animals with agmatine destructive processes, inflammation and DNA damage, restores redox homeostasis and a balances antioxidant decrease activity of transporter proteins, and alter ATP-ase defence system enzymes in leukocytes. This corrective activity leading to disregulation of the electron transport effect on the functional capacity of leukocytes is exerted by chain cascade. Furthermore, in presence of Fe3+ and Cu2+, preventing oxidative-nitrative stress in animals with DM. glucose and its metabolites react with hydrogen peroxide • (Н2О2) forming hydroxyl radical ( ОН) to increase oxidative Keywords: agmatine, NO-synthase, antioxidant enzymes, destruction of macromolecules through disruption of any leukocytes, streptozotocin-induced DM С–Н and С–С bonds [7–9]. Glucose autooxidation and non-enzymatic glycosylation of amino groups of proteins and phospholipids also leads to an accumulation of metabolism end products (advanced oxidation protein *Corresponding author: Iryna Brodyak, Department of Biochemistry, products (AOPPs) and advanced glycosylation end- Faculty of Biology, Ivan Franko National University of Lviv, Ukraine, products (AGEs)) which are difficult to eliminate from 4, Hrushevskyi Str., Lviv 79005, Ukraine; the blood and remain in circulation [10]. They are also E-mail: [email protected] the source of reactive oxygen species (ROS) since they Ivanna Bila, Olha Dzydzan, Natalia Sybirna, Department of Biochemistry, Faculty of Biology, Ivan Franko National University of imitate metal containing oxidation systems. Excessive •− • Lviv, Ukraine formation of ROS (O2 , ОН, Н2О2) and reactive nitrogen Open Access. © 2019 Ivanna Bila et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 Public License. 300 I. Bila, et al. species (RNS – NO, ONOO–, nitroxyl donors) also leads of antioxidants, attention will be given to agmatine to the development of oxidative-nitrative stress [3, 4, 11]. (4-aminobutyl guanidine), a product of L-arginine Therefore, DM is typically characterized by an intensive decarboxylation [27–30]. Agmatine inhibits mRNA free radical oxidation of biosubstrates [12]. Simultaneously, expression of iNOS and prevents development of oxidative the depletion of antioxidant defence mechanisms also stress under sepsis-induced vascular dysfunction [30]. occurs during diabetes [13]. A decrease of GSH levels and Furthermore, agmatine alleviates oxidative stress and activity of antioxidant protection enzymes: glutathione inhibits the production of cytokines and inflammation peroxidase (GPx), superoxide dismutase (SOD), catalase under conditions of acute kidney injury in rats [31]. The (CAT), nicotinamide adenine dinucleotide phosphatase ability to act as an endogenous nitric oxide synthase and others was observed [5, 14–16]. These changes inhibitor (NOS) is a distinctive feature of agmatine when produce a favorable background for the formation of compared to other prophylactic and hypoglycemic agents atherosclerotic, micro- and macrovascular diabetic [28, 31–33]. Since agmatine, as L-arginine, contains a complications [11, 17, 18]. guanidine group it serves as a competitive inhibitor of The alteration in structural and functional activity NOS (Ki = 660 µM for nNOS, 220 µM for iNOS and 7.5 mM of leukocytes is an important part of the pathogenesis for eNOS). Possessing the most potent inhibitory action of diabetic complications. Changes in intracellular toward iNOS activity, this amine can be an endogenous metabolism, intensification of glycation processes and regulator of nitric oxide production by iNOS in leukocytes the development of oxidative-nitrative stress in blood cells during their activation and functioning in normal and under conditions of prolonged hyperglycemia, are the disease conditions [30]. Therefore, arginine decarboxylase main factors which induce pathological changes in the which catalyzes the conversion of L-arginine to agmatine, structure of their components and affect their functional and agmatinase that degrades agmatine, are both present state [5, 19]. In particular, changes in the morphofunctional in cells that express cNOS and iNOS [34, 35]. state of leukocytes can be explained by defects in the The main aim of our work was to investigate the physiological balance between levels of antioxidants effects of agmatine on NOS activity and the enzymatic and free radical compounds [20]. The maintenance of antioxidant defence system, and also to determine the intracellular ROS levels within normal limits is crucial content on nitrites and nitrates, AOPPs, AGEs, GSH and for some cytoskeleton-dependent processes, for example, thiobarbituric acid reactive substance (TBARS) of lipid leukocyte migration from the blood into inflammation peroxidation (LPO) in leukocytes of peripheral blood of zones, where they exert their main functions as rats under DM. immunocompetent cells [21]. In our previous research we established [22] that in leukocytes from animals with DM, the total content of actin is reduced, whereas actin 2 Materials and methods polymerization is intensified in membrane cytoskeletal filaments. The development of oxidative-nitrative stress 2.1 Animal experiments is one of the reasons for the alteration of this dynamic process of actin polymerization-depolymerization in 2.1.1 Induction of diabetes in rats leukocytes during DM. Excessive oxidation of proteins in stress conditions leads to the destruction of F-actin of the Wistar male rats with a starting weight of 120–130 g were cytoskeleton, thereby breaking locomotive and protective used for all experiments. Animals were given free access functions of leukocytes [22–24]. The overproduction of to a standard chow and water and housed under a 12 h ROS and RNS increases the probability of oxidation of thiol light/dark cycle. The room temperature and humidity groups in tubulin monomers and promotes the formation were maintained were maintained automatically at about of disulfide bonds between α- and β-tubulin, which 22 ± 2°C and 60 ± 5%, respectively. After several days of decreases the ability of microtubules to polymerize and adaptation, DM was induced by a single intraperitoneal alters the structure of actin [25]. The targets of oxidation injection of 6 mg freshly prepared streptozotocin (Sigma in F-actin molecules are Cys374 and Met44 residues. The Aldrich GmbH, Germany) per 100 g of body weight oxidation of Cys374 results in glutathionylation of actin (b.w.), dissolved in 10 mM Na-citrate buffer (pH 5.5). filaments, and oxidation of Met44 leads to the severing Animals in the control group were injected with buffer of actin filaments [26]. The development of oxidative- alone. The development of diabetes was detected by nitrative stress in peripheral blood cells during DM can be the blood glucose measurements made 72 h after the prevented by endogenous antioxidants. Among a variety administration of streptozotocin. Animals exhibiting Agmatine prevents
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