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  • br Conclusion In conclusion the arginase from

    2023-01-28


    Conclusion In conclusion, the arginase from P. aeruginosa IH2 was purified with electrophoretic homogeneity. Purified enzyme was homo-dimer and showed significant activity and catalytic stability near to the pH of circulating system and temperature of human body. The prolonged serum and proteolytic half-life are therapeutically remarkable features of our arginase. Interestingly, purified arginase exhibited substantial anticancer activity against cancer cell lines of various tissues. Mechanistically, in HL-60 cells, arginase arrest PCI-34051 sale in G0/G1 phase and generate ROS mediated depolarization of mitochondrial membrane potential, which led to apoptotic cell death. One of the striking findings of this research is that purified arginase did not exert cytotoxic effect on normal cells. Therefore, the present study raises the reinforced possibility to use purified arginase as a potent antileukemic agent. Moreover, further studies are required which are under way to address this possibility.
    Conflicts of interest
    Author contributions
    Acknowledgments
    Introduction Advanced glycation end products (AGEs) are compounds that are formed in serum and tissues by non-enzymatic reactions (called glycation). This includes the reduction of sugars with amino group of nucleic acids lipids, and proteins [1,2]. AGEs are formed in the normal body from early embryonic development, and further accumulate with aging. However, levels of AGEs are also enhanced in diabetic patient [3] and smokers [4]. In addition, different studies reveal a significant role of AGEs in the formation of atherosclerotic lesions, an effect mediated by changes in various cell types such as the endothelial cell and macrophage. Accumulation of AGEs also caused arterial stiffening with loss of elasticity of large vessels [5]. Endothelial dysfunction represents a harmful alteration in endothelial physiology and a key factor in the development of atherosclerosis. It is characterized by impaired endothelial-dependent vasodilation in which nitric oxide (NO) plays a crucial role [6,7] and maintains vascular homeostasis. It also has a key role in inflammation and oxidative stress through the release of reactive oxygen species (ROS). Nitric oxide is synthesized as a soluble gas from the amino acid l-arginine in endothelial cells by the calcium-calmodulin-dependent NO synthases (NOS) [8]. Nitric oxide then stimulates soluble guanylyl cyclase (sGC) to produce cyclic guanosine 3′,5′-monophosphate (cGMP) as a second messenger [[9], [10], [11]]. l-arginine is also substrate for arginase enzymes which metabolize it to urea and ornithine. Hence increased arginase activity reduces tissue availability of l-arginine and is associated with inhibition of NO production by eNOS [12,13].
    Methods
    Results
    Discussion In the present study we found that AGEs impaired endothelial-dependent vasodilation response while enhancing endothelial-independent vasodilation. Here, we have determined for the first time that the impaired vasodilation effect of AGEs is mediated via arginase and NADPH oxidase (NOX) activation, as shown by exposing aortae to either arginase or NOX inhibitors. The remarkable impairment effect of AGEs on vasodilation was shown to be via inhibition of ACh-induced NO production. As with to effects on endothelial-dependent vasodilation, the effect of AGEs on NO production was inhibited by arginase or NOX inhibitors. We also found that AGEs induced mRNA expression of Arg2 but down-regulated eNOS expression. This further confirmed the role of arginase in impairment of vasodilation by AGEs. Arginase activation reduces the availability of l-arginine for eNOS, thus reducing NO production and vascular relaxation. In the current study, arginase inhibition by l-ornithine prevented the AGEs-induced impairement of endothelial-dependent vasodilation. In addition, AGEs exposure led to arginase overexpression in the rat aorta. Similarly, a previous study showed that AGEs-mediate endothelial dysfunction in preeclampsia might be attributed to increased arginase 2 expression, which caused endothelial dysfunction via attenuating NO production [43].