enkephalin--leucine-2-alanine and Liver-Diseases

Hepatic ischemia/reperfusion (I/R) injury is a common pathophysiological process that occurs following liver surgery, which is associated with oxidative stress, and can cause acute liver injury and lead to liver failure. Recently, the development of drugs for the prevention of hepatic I/R injury has garnered interest in the field of liver protection research. Previous studies have demonstrated that [D‑Ala2, D‑Leu5]‑Enkephalin (DADLE) exerts protective effects against hepatic I/R injury. To further clarify the specific mechanism underlying the effects of DADLE on hepatic I/R injury, the present study aimed to observe the effects of various doses of DADLE on hepatic I/R injury in mice. The results indicated that DADLE, at a concentration of 5 mg/kg, significantly reduced the levels of alanine aminotransferase and aspartate aminotransferase in the serum, and the levels of malondialdehyde in the liver homogenate. Conversely, the levels of glutathione, catalase and superoxide dismutase in the liver homogenate were increased. In addition, DADLE was able to promote nuclear factor, erythroid 2 like 2 (Nrf2) nuclear translocation and upregulate the expression of heme oxygenase (HO)‑1, which is a factor downstream of Nrf2, thus improving hepatic I/R injury in mice. In conclusion, the present study demonstrated that DADLE was able to significantly improve hepatic I/R injury in mice, and the specific mechanism may be associated with the Nrf2/HO‑1 signaling pathway.

Topics: Animals; Aspartate Aminotransferases; Disease Models, Animal; Enkephalin, Leucine-2-Alanine; Heme Oxygenase-1; Liver; Liver Diseases; Male; Malondialdehyde; Membrane Proteins; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidative Stress; Reperfusion Injury; Signal Transduction; Superoxide Dismutase; Up-Regulation

Apoptosis of human liver cells is commonly found in liver diseases and liver surgery and directly affects their prognosis. Recent studies have found that δ-opioid receptors, abundant in the membranes of hepatic cells, participate in the oncogenesis and progression of liver tumors, viral hepatitis, liver cirrhosis and other diseases. The purpose of this study was to analyze the effect of the activation of the δ-opioid receptor on liver cell apoptosis and explore its relationship with PKC and the mitochondrial pathway. Hepatic cells were serum-deprived to induce apoptosis in vitro. During the period of apoptosis, mitochondrial membrane potential decreased, protein levels of cytosolic cytochrome c increased and the expression of Bcl-2 decreased, indicating that apoptosis was specifically induced by the mitochondrial pathway. Importantly, activation of δ-opioid receptors reversed the apoptotic state of hepatic cells. Following δ-opioid receptor activation, the mitochondrial membrane potential remained stable, and the expression of cytosolic cytochrome c and Bax decreased. These data suggest that δ-opioid receptor activation specifically inhibits the mitochondrial apoptotic pathway. In addition, activation of the δ-opioid receptor apparently increased the levels of PKC; blocking the PKC pathway led to increased apoptosis of liver cells, which was not affected by the activation of δ-opioid receptor. Blocking the PKC pathway led to increased apoptosis of liver cells, which was associated with δ-opioid receptor activation. Therefore, the PKC pathway is involved in the anti-apoptotic effects of the δ-opioid receptor on liver cells.

Topics: Apoptosis; bcl-2-Associated X Protein; Cytochromes c; Enkephalin, Leucine-2-Alanine; Gene Expression; Hepatocytes; Humans; Liver; Liver Diseases; Membrane Potential, Mitochondrial; Mitochondria; Naltrexone; Protein Kinase C; Proto-Oncogene Proteins c-bcl-2; Receptors, Opioid, delta; Serum; Signal Transduction; Stress, Physiological; Tumor Cells, Cultured

[D-Ala(2), D-Leu(5)] enkephalin (DADLE) is a synthetic delta class of opioid and is reported to induce hibernation as well as hibernation induction trigger (HIT) in the serum of hibernating mammals. DADLE and HIT have been demonstrated to protect the heart, lung, and jejunum against ischemia-reperfusion (I-R) injury. In the present study, we examined the effect of DADLE on I-R injury of the liver in rats.. After administration of DADLE (DADLE group) or normal saline as a vehicle (Control group), partial hepatic ischemia was induced by occluding the vessels supplying 92% of the liver for 45 min, followed by declamping the vessels and resection of the non-ischemic lobe. After 120 min of reperfusion, serum glutamic-pyruvic transaminase (GPT), hyaluronic acid (HA) levels, and concentrations of malondialdehyde (MDA) of the liver tissue were measured. Additionally, bile output from the ischemic lobes was measured after reperfusion.. GPT levels were significantly lower in the DADLE group as compared to those of the Control group (P < 0.05), but the serum levels of HA were not different between the two groups. The concentrations of MDA of the liver tissue were significantly lower in the DADLE group than in the Control group (P < 0.01). The bile output after reperfusion was not significantly different between the two groups.. DADLE protects against I-R injury in hepatocytes, but not in the sinusoidal endothelial cells of the liver in rats. An anti-oxidative effect is suggested to be responsible for this effect.

Topics: Alanine Transaminase; Analgesics, Opioid; Animals; Bile; Cytoprotection; Enkephalin, Leucine-2-Alanine; Hibernation; Hyaluronic Acid; Liver; Liver Diseases; Male; Malondialdehyde; Rats; Rats, Wistar; Reperfusion Injury

The newborn rats after 48 hours after the birth were used in the study. The prenatal hypoxia caused the development of hypotrophy. Index of labeled 3H-thymidine nuclei decreased 1.5 fold, mitotic index decreased 1.4 fold. The content of aberrant figures of mitosis increased 2.6 times. Hexapeptide injection before hypoxia reduced the alterations caused by hypoxia, the data of body and liver weight did not differ from the control level.

Topics: Animals; Animals, Newborn; Antioxidants; Enkephalin, Leucine-2-Alanine; Fetal Hypoxia; Liver; Liver Diseases; Organ Size; Rats; Vitamin E

Results obtained from the study of mechanisms of hepatoprotective effect of transcranial transcutaneous electrostimulation are cited (TTES). In experiments on cholestase and pancreatitis models in rats we studied hepatospecific enzymes i.e. histidase and urokininanse in blood and liver and membrane-linked enzyme 5'-nucleotidase in the liver tissue. We made three series of experiments: 1 - TTES + valium, 2 - synthetis hexapeptide (SH) - leuenkephaline analog; 3 - TTES + valium + SH. Results obtained from experiments showed that mechanisms of TTES hepatoprotective action are in part conditioned by endogenous opiopeptides mobilization which produced membranestabilizing effect on the hepatocyte. We concluded that in patients with hepatic pathology it was reasonable to combine the electroanesthesia with SH.

Topics: Animals; Brain; Electric Stimulation Therapy; Electronarcosis; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Histidine Ammonia-Lyase; Liver; Liver Diseases; Male; Rats; Transcutaneous Electric Nerve Stimulation; Urokinase-Type Plasminogen Activator