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Background: This study aimed to evaluate the protective effect and mechanisms of remote limb ischaemic postconditioning (RIPostC) against myocardial ischaemia/reperfusion (IR) injury. Methods: Male mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. RIPostC was achieved by three cycles of 5 min of ischaemia and 5 min of reperfusion in the left hind limb at the start of the reperfusion period. After 2 h of cardiac reperfusion, myocardial infarct size, cardiac enzyme release, apoptosis and oxidative stress were assessed. Protein expression and phosphorylation were measured by Western blotting. Results: RIPostC significantly decreased cardiac IR injury, as reflected by reduced infarct size and cellular apoptosis (22.9 ± 3.3% vs 40.9 ± 6.2% and 13.4% ± 3.1% vs 26.2% ± 3.1%, respectively, both P < 0.01) as well as plasma creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release (21.97 ± 4.08 vs 35.86 ± 2.91 ng/ml and 6.17 ± 0.58 vs 8.37 ± 0.89 U/ml, respectively, both P < 0.01) compared with the IR group. RIPostC significantly increased the phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.01). In addition, RIPostC elevated the nuclear translocation of Nrf2 and the expression of HO-1 and reduced myocardial oxidative stress (P < 0.05). Interestingly, pretreatment with the JAK/STAT3 inhibitor AG490 blocked the cardioprotective effect of RIPostC accompanied by decreased phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.05), decreased nuclear translocation of Nrf2 and expression of HO-1, as well as increased oxidative stress (P < 0.05). Conclusion: RIPostC attenuates apoptosis and protects against myocardial IR injury, possibly through the activation of JAK/STAT3-mediated Nrf2-antioxidant signalling.

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Summary5-Methoxymethyl-2'-deoxycytidine (MMdCyd) and the corresponding deoxyuridine analogue, 5-methoxymethyl-2'-deoxyuridine (MMdUrd) are selective antiherpesvirus agents. MMdCyd (ED 50 1.5~lM) is a more potent inhibitor of herpes simplex virus replication than MMdUrd (ED 5o 30~lM) when maintained in the deoxycytidine form (deamination prevented). The 5'-triphosphates, MMdCTP and MMdUTP, were synthesized, and incorporation into DNA. by mitochondrial DNA polymerase y was investigated. MMdcTPand MMdUTP were incorporated into DNA in place of dCTP and dTTP, respectively. The effect of MMdCyd and MMdUrd on cell growth (acute toxicity) and proloriged exposure (delayed cytotoxicity) in CEM cells was investigated. The two analogues did not exhibit acute or delayed toxicity (2 weeks exposure) up to 1000~lM. In contrast, at a concentration as low as 0.125~lM of 2' )'-dideoxycytidine (ddC; control druq], the doubling time of the cells increased after 10 days. At higher concentrations, a very marked increase in doubling time was observed from 6 days onward with ddC treatment. The data suggest that in uninfected cells neitherMMdUrd nor MMdCyd are anabolized to the triphosphate Form in signiFicant amounts. As a result, little or no MMdCTP or MMdUTP builds up in the mitochondria and thus delayed toxicity is not observed.

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