Protection of rat liver against hepatic ischemia-reperfusion injury by a novel selenocysteine-containing 7-mer peptide

Abstract

Hepatic ischemia-reperfusion (I-R) injury causes acute organ damage or dysfunction, and remains a problem for liver transplantation. In the I-R phase, the generation of reactive oxygen species aggravates the injury. In the current study, a novel selenocysteine-containing 7-mer peptide (H-Arg-Sec-Gly-Arg-Asn-Ala-Gln-OH) was constructed to imitate the active site of an antioxidant enzyme, glutathione peroxidase (GPX). The 7-mer peptide which has a lower molecular weight, and improved water-solubility, higher stability and improved cell membrane permeability compared with other GPX mimics. Its GPX activity reached 13 U/µmol, which was 13 times that of ebselen (a representative GPX mimic). The effect of this GPX mimic on I-R injury of the liver was assessed in rats. The 7-mer peptide significantly inhibited the increase in serum hepatic amino-transferases, tissue malondialdehyde, nitric oxide contents, myeloperoxidase activity and decrease of GPX activity compared with I-R tissue. Following treatment with the 7-mer peptide, the expression of B-cell CLL/lymphoma-2 (Bcl-2) was significantly upregulated at the mRNA and protein level compared with the I-R group, as determined by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. By contrast, Bcl-2 associated X protein (Bax) was downregulated by the 7-mer peptide compared the I-R group. Histological and ultrastructural changes of the rat liver tissue were also compared among the experimental groups. The results of the current study suggest that the 7-mer peptide protected the liver against hepatic I-R injury via suppression of oxygen-derived free radicals and regulation of Bcl-2 and Bax expression, which are involved in the apoptosis of liver cells. The findings of the present study will further the investigation of the 7-mer peptide as an effective therapeutic agent in hepatic I-R injury.

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

“…Protein kinase A, a specific peptide inhibitor, effectively abolishes cytosol‐induced inhibition of MPT and hepatic IR injury . Owing to its high water‐solubility and stability, a novel selenocysteine containing the 7‐mer peptide attenuates hepatic IR‐induced injury by suppressing free radicals and up‐regulating Bcl2/Bax expression . Polyethylene glycol‐conjugated cysteine‐modified lysine dendrimers eliminate ROS production and prolong circulation time in hepatic IR injury .…”

Ebselen impairs cellular oxidative state and induces endoplasmic reticulum stress and activation of crucial mitogen‐activated protein kinases in pancreatic tumour AR42J cells

“…For example, ebselen attenuates Mn‐induced toxicity in Caenorhabditis elegans by preventing oxidative stress . Protection of rat liver against hepatic ischemia‐reperfusion injury has been shown . Glucose‐induced osmotic fragility of human erythrocytes was improved by ebselen in vitro .…”

Selenocysteine modulates resistance to environmental stress and confers anti-aging effects in C. elegans

“…In aged rats, selenium reduces oxidative stress, apoptosis, and memory impairment 19 . Synthetic oligopeptides containing selenocysteine decrease the production of reactive oxygen species and suppress apoptosis through the regulation of the Bcl-2/Bax ratio 20 . In humans, mutations in selenocysteine synthase, an enzyme catalyzing the synthesis of selenocysteine, cause early-onset neurological damages, such as cerebellar atrophy 21 .…”