Significance: 8-Hydroxy-2-deoxyguanosine (8-OHdG) is generated after the repair of ROS-mediated DNA damages and, thus, is one of the most widely recognized biomarkers of oxidative damage of DNA because guanosine is the most oxidized among the DNA nucleobases. In several pathological conditions, high urinary levels of oxidized DNA-derived metabolites have been reported (e.g., cancer, atherosclerosis, hypertension, and diabetes). Recent Advances: Even if published studies have shown that DNA damage is significantly associated with the development of atherosclerosis, the exact role of this damage in the onset and progression of this pathology is not fully understood, and the association of oxidative damage to DNA with cardiovascular disease (CVD) still needs to be more extensively investigated. We performed a meta-analysis of the literature to investigate the association among 8-OHdG levels and CVD. Critical Issues: Fourteen studies (810 CVD patients and 1106 controls) were included in the analysis. We found that CVD patients showed higher 8-OHdG levels than controls (SMD: 1.04, 95%CI: 0.61, 1.47, p < 0.001, I2 = 94%, p < 0.001). The difference was confirmed both in studies in which 8-OHdG levels were assessed in urine (MD: 4.43, 95%CI: 1.71, 7.15, p = 0.001) and in blood samples (MD: 1.42, 95%CI: 0.64, 2.21, p = 0.0004). Meta-regression models showed that age, hypertension, and male gender significantly impacted on the difference in 8-OHdG levels among CVD patients and controls. Future Directions: 8-OHdG levels are higher in patients with CVD than in controls. However, larger prospective studies are needed to test 8-OHdG as a predictor of CVD. Antioxid. Redox Signal. 24, 548–555.
AbstractEssential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2–dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
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