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  • Diabetes or inflammation is associated with up regulation of


    Diabetes or inflammation is associated with up-regulation of A2AAR (Pang et al., 2010). High levels of A2AARs are found in macrophages and microglial cells that are poised, on activation, to abrogate the immune response (Trincavelli et al., 2008). In addition, hyperglycemia is associated with increased ENT1, possibly via an MAPK/ERK-dependent signaling pathway (Leung et al., 2005). ABT 702 inhibited the expression of both A2AAR and ENT1 in the diabetic retina suggesting its ability to attenuate diabetic conditions. Further, we demonstrated that ABT 702 injection attenuated diabetes-induced reduction in AK expression. In the brain, AK expression is decreased following onset of injury thus potentiating the adenosine surge as a potential neuroprotective mechanism. Indeed, expression levels of AK might have a crucial role in determining the degree of c75 mg injury (Li et al., 2008). Next, we studied the effect of ABT 702 on oxidative and nitrosative stress in the retina in diabetes. In diabetes the retina experiences increased oxidative stress (Kowluru and Kanwar, 2007), and reactive oxygen species (ROS) are considered as a causal link between elevated glucose and the metabolic abnormalities important in the development of diabetic complications (Brownlee, 2001). ABT 702 decreased superoxides and nitrotyrosine levels in diabetic retina. The ability of ABT 702 to reduce inflammatory stress in the retina may rely on its inhibitory effect on oxidative and nitrosative stress. Further, we studied the effect of ABT 702 on retinal cell death. Diabetes-induced retinal oxidative and nitrosative stress have been positively correlated with neuronal cell death (Asnaghi et al., 2003). Treating diabetic mice with ABT 702 blocked the increases in oxidative and nitrosative stress and significantly reduced cell death as revealed by decreased cleaved caspase-3 immunostaining and TUNEL assay in treated diabetic retinas. Neurons are highly susceptible to oxidative stress, which can induce apoptosis; therefore, it is likely that diabetes-induced oxidative stress leads to neuronal injury. Finally, despite all the advantages for ABT 702 as a potential effective therapy for DR, given that the administration of ABT 702 by i.p. injection is invasive and stressful, oral administration of ABT 702 may be necessary but should be carefully developed (Kowaluk et al., 2000).
    Conflict of interest
    Acknowledgments This work was supported by Egyptian Cultural and Educational Bureau (NME and GIL), Department of Defense DM102155 (GIL) and Vision Discovery Institute (GIL).
    Introduction Toxoplasma gondii adenosine kinase (TgAK, EC catalyzes the phosphorylation of adenosine (Ado), to its nucleoside 5′-monophosphate, AMP, in the presence of ATP as follows:
    Materials and methods
    Results and discussion
    Conclusions The present initial velocity studies indicate that the double reciprocal plot of TgAK yields a non-competitive pattern, while the product inhibition studies with fixed changing AMP yield a competitive pattern with 1/v vs. [1/ATP] at a fixed Ado concentration and a non-competitive pattern with 1/v vs. 1/[Ado] at a fixed ATP concentration as summarized in Table 3. These results are compatible with a random system (Segel, 1993). In light of these results, we propose that the TgAK reaction mechanism is a hybrid random bi-uni ping-pong uni-bi, as depicted below: Our present results clearly indicate that the mechanism of action of TgAK is random not ordered. It is more plausible that whenever ATP and Ado enter their respective sites, ATP donates the γ-phosphate to Ado. The formed AMP is readily released from the Ado site as its Kii is 0.5mM. However, before the ADP, produced from the dephosphorylation of ATP, is released, a second Ado enters the vacant Ado site and is instantaneously phosphorylated by the enzyme-bound-ADP, as inferred from the almost perfect correlation between doubling the ADP concentration and halfing of the distance between the activity lines, from which it might be construed that ADP supplants ATP in the reaction (Fig. 7). Thus, the order of occupancy of the Ado site is not that Ado always enters before the phosphate donor. It may enter first when ATP is the phosphate donor, but it is certainly second in the order of occupancy when the ADP, produced from ATP c75 mg dephosphorylation, is the phosphorylating agent. This is precisely the reason that the TgAK reaction is not an ordered, but rather a random mechanism, as clearly indicated by the present results (Table 3). This is further supported by direct evidence as crystallographic studies (Zhang et al., 2006) showed that Ado binding and ATP binding are two independent processes associated with separate conformational changes. Furthermore, in all the available TgAK structures studied (Zhang et al., 2007), no structure was seen with an occupied nucleoside-binding site and an empty ATP-binding. Only when Ado is present, it occupied both the ATP and nucleoside-binding sites.