Oxidative stress has recently been reported as

Oxidative stress has recently been reported as one of the important mechanisms of toxic effect of Cd2+[43]. The mechanism of Cd2+-induced oxidative stress involves an imbalance between generation and removal of ROS in tissues and cellular components, causing damage to membranes, DNA, and proteins [43]. ROS generated by Cd initiate lipid peroxidation of the membrane-bound polyunsaturated fatty acids, leading to impairment of the membrane structural and functional integrity, which is the result of an interaction between free radicals of diverse origins and unsaturated fatty acids that are typical in membrane lipids. Degradation of polyunsaturated fatty acids in cell membranes by ROS, induced by Cd, results in the destruction of membranes and the formation of thiobarbituric Fmoc-Phe-OPfp mg reactive species, MDA, or conjugated dienes as indicators of lipid peroxidation [44]. In the present study, the level of MDA was measured as an indicator of lipid peroxidation (Figure 4). The level of MDA was significantly increased in the kidney tissue of Cd-intoxicated rats. Our experimental findings suggest that oxidative stress plays an important role in cadmium-induced renal injuries. Our result is in accordance with other findings reporting Cd-induced oxidative damage [43], [45], [46]. The increased MDA levels in renal tissue is an indication of overaccumulation of lipid peroxides in tissue, causing overconsumption and depletion of functional thiol (-SH) groups in several antioxidant enzymes, as observed in Figure 5. Reduced glutathione (GSH) or non-protein thiol is a multifunctional intracellular nonenzymatic antioxidant, which is considered to be the major thiol–disulfide redox buffer of the cell. It serves many vital physiological functions, including protection of cells from ROS, detoxification of exogenous compounds, and amino acid transport with the help of the SH group present in them, which is essential for its antioxidant activity against some forms of ROS in the cells [47]. Decreased GSH and total thiol levels, as observed in the Cd-treated rats (Figure 5), are due to enhanced utilization of these antioxidants for scavenging free radicals. GSH forms complexes with Cd through the free SH group, while ROS generated by Cd deplete the intracellular SH groups as well as disrupt intracellular organelles, thereby altering Cd distribution and excretion [48]. However, treatment with curcumin enhances the level of GSH and effectively provides thiol groups for the possible GSH-mediated detoxification reactions. The antioxidant mechanism of curcumin has been attributed to its conjugated structure, which includes two methoxylated phenols and an enol form of β-diketone [49]. The structure showed a typical radical-trapping ability as a chain-breaking antioxidant [49]. Furthermore, it has been reported that curcumin is a bifunctional antioxidant, because of its ability to react directly with reactive species and to induce upregulation of various cytoprotective and antioxidant proteins via activation of the Keap1/Nrf2/ARE pathway [50], [51]. Curcumin is able to inhibit generations of superoxide anion () and hydroxyl radical (·OH) through prevention of the oxidation of Fe2+ in Fenton's reaction [52]. The kidney is considered as one of the major target organs affected by Cd2+ toxicity. Cd can accumulate in the kidneys and cause severe tissue damage in these organs, as observed from the results reported in this study. It is noted that the Cd content in the whole kidney of the group that received Cd was significantly increased (p < 0.05) when compared with the control. Numerous studies have unraveled the exact pathways by which cadmium enters the renal epithelial cells and the possible mechanism by which it causes toxicity in the kidney [3], [45], [46]. Interestingly, this study has found that the Cd contents in the kidney of Cd-intoxicated groups were decreased in rats receiving curcumin (Figure 6). Based on the electrochemical studies, it has been suggested that there might be a metal–ligand interaction between Cd and curcumin, thereby reducing the heavy metal load in the body and the toxic effects of Cd [53]. Moreover, it is possible that curcumin might interfere with the gastrointestinal absorption of Cd, thereby causing a reduction in Cd concentration in the tissues. This suggests the potential chelating effect of curcumin, as reported in some recent studies [51], [54], [55].