Abstract
A possibility of repurposing sitagliptin, a well-established antidiabetic drug, for alleviating injury caused by ischemia-reperfusion (IR) is being researched. The aim of this study was to shed some light on the molecular background of the protective activity of sitagliptin during hepatic IR. The expression and/or concentration of inflammation and oxidative stress-involved factors have been determined in rat liver homogenates using quantitative RT-PCR and Luminex® xMAP® technology and markers of nitrative and halogenative stress were quantified using targeted metabolomics (LC-MS/MS). Animals (n = 36) divided into four groups were treated with sitagliptin (5 mg/kg) (S and SIR) or saline solution (C and IR), and the livers from IR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). The midkine expression (by 2.2-fold) and the free 3-nitrotyrosine (by 2.5-fold) and IL-10 (by 2-fold) concentration were significantly higher and the Nox4 expression was lower (by 9.4-fold) in the IR than the C animals. As compared to IR, the SIR animals had a lower expression of interleukin-6 (by 4.2-fold) and midkine (by 2-fold), a lower concentration of 3-nitrotyrosine (by 2.5-fold) and a higher Nox4 (by 2.9-fold) and 3-bromotyrosine (by 1.4-fold). In conclusion, IR disturbs the oxidative, nitrative and halogenative balance and aggravates the inflammatory response in the liver, which can be attenuated by low doses of sitagliptin.
Highlights
Introduction published maps and institutional affilThe liver is the second most frequently transplanted organ worldwide
We found that hepatic IR injury is associated with disturbed nitrative and halogenative balance in addition to oxidative stress and inflammatory response and demonstrated sitagliptin’s ability to attenuate it by reducing the expression of inflammatory agents and modulating oxidative, nitrative and halogenative stress
IR injury caused a significant, 2.2-fold elevation in its expression, which was restored to control animal level in rats pretreated with sitagliptin (Figure 2a)
Summary
Introduction published maps and institutional affilThe liver is the second most frequently transplanted organ worldwide. The transplantation procedure is the best and often the last option available for patients with end-stage liver disease. Its frequency is steadily increasing, the number of patients awaiting transplantation vastly exceeds organ availability [1]. Liver transplantation is associated with the risk of graft rejection and ischemia/reperfusion (IR). It is estimated that the accompanying IR injury is responsible for 10% of early organ failure [1]. The initial damage is caused by ischemia and aggravated by reperfusion, which involves an early acute (3–6 h after reperfusion) and a subacute phase (18–24 h after reperfusion). Reperfusion, in each phase, is accompanied by the accelerated generation of reactive oxygen (ROS), nitrogen (RNS) and halogen (RHS) species.
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