Nano-Curcumin Prevents Cardiac Injury, Oxidative Stress and Inflammation, and Modulates TLR4/NF-κB and MAPK Signaling in Copper Sulfate-Intoxicated Rats

Abstract

Copper (Cu) is essential for a plethora of biological processes; however, its high redox reactivity renders it potentially toxic. This study investigated the protective effect of curcumin (CUR) and nano-CUR (N-CUR) against Cu cardiotoxicity, emphasizing the role of oxidative stress, TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling and cell death in rats. Rats received 100 mg/kg copper sulfate (CuSO4), a pesticide used for repelling pests, and were concurrently treated with CUR or N-CUR for 7 days. Cu caused cardiac injury manifested by elevated serum cardiac troponin I (cTnI), creatine kinase (CK)-MB, and lactate dehydrogenase (LDH), as well as histopathological alterations. Cardiac malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 were increased, and reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were decreased in Cu-treated rats. CUR and N-CUR prevented cardiac tissue injury, decreased serum cTnI, CK-MB, and LDH, and cardiac MDA, NF-κB p65, TNF-α, and IL-6, and enhanced cellular antioxidants. CUR and N-CUR downregulated TLR4 and AP-1, and decreased the phosphorylation levels of p38 MAPK, JNK, and ERK1/2. In addition, CUR and N-CUR increased cardiac Bcl-2 and BAG-1, decreased Bax and caspase-3, and prevented DNA fragmentation. In conclusion, N-CUR prevents Cu cardiotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis, and modulating TLR4/NF-κB and MAPK signaling. The cardioprotective effect of N-CUR was more potent than the native form.

Nano-Curcumin Prevents Copper Reproductive Toxicity by Attenuating Oxidative Stress and Inflammation and Improving Nrf2/HO-1 Signaling and Pituitary-Gonadal Axis in Male Rats

“…CuSO 4 increased Bax and caspase-3 and decreased the anti-apoptotic marker Bcl-2. Similar findings have been previously reported in the brain and heart of rats treated with CuSO 4 [ 15 , 16 ]. ROS and pro-inflammatory mediators can activate Bax which promotes the loss of mitochondrial membrane potential and subsequently cytochrome c is released to the cytosol where it activates the executioner caspase-3 [ 71 ].…”

“…Oxidative stress has been suggested to play a key role in Cu toxicity [ 15 , 16 ], and some researchers have demonstrated that its testicular toxicity occurs via provoking oxidative damage [ 19 , 24 ]. Cu is able to cycle easily between unstable reduced and stable oxidized states and facilitate redox reactions.…”

“…Inflammation and apoptosis are implicated in the toxic effects of Cu, including neurotoxicity [ 15 ], cardiotoxicity [ 16 ] and testicular toxicity [ 24 ]. Here, NF-κB, iNOS, and TNF-α were significantly upregulated in the testes of rats that received CuSO 4 , denoting an inflammatory response.…”

“…Excess ROS can activate many signaling molecules, including NF-κB which subsequently elicits the transcription of iNOS and inflammatory cytokines [ 70 ]. Recently, we have reported the activation of TLR4/NF-κB and MAPK signaling and the release of pro-inflammatory cytokines in the cardiac tissue of Cu-administered rodents [ 16 ]. In conjunction with inflammation, testicular apoptosis was observed in CuSO 4 -administered rats.…”

“…Accordingly, exposure of rats to CuSO 4 resulted in increased Cu levels in the liver and kidney and subsequently impairment and damage of these organs [ 14 ]. Recent work from our lab has demonstrated neurotoxicity and cardiac injury in rats exposed to CuSO 4 [ 15 , 16 ].…”