PMID- 24967531 OWN - NLM STAT- MEDLINE DCOM- 20160204 LR - 20220316 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 740 DP - 2014 Oct 5 TI - Limonin attenuates hepatocellular injury following liver ischemia and reperfusion in rats via toll-like receptor dependent pathway. PG - 676-82 LID - S0014-2999(14)00452-X [pii] LID - 10.1016/j.ejphar.2014.06.010 [doi] AB - Limonin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of chemically induced hepatic injury. The current study aimed to investigate the protective effects of limonin on experimentally-induced hepatic ischemia reperfusion (I/R) injury in rats. Rats were injected IP with either DMSO or limonin (100 mg/kg BW), 30 min before submission to 45 min of ischemia, followed by 1 h of reperfusion. Limonin ameliorated the deleterious effects of I/R as indicated by improvement in liver function tests, reduction of lactate dehydrogenase, reduction of oxidative stress, decrease in hepatocyte degeneration, and pyknosis. Furthermore, pretreatment of I/R rats with limonin, induced a significant down regulation in the various elements of the toll like receptor (TLR)pathway including TLR-2 and TLR-4, myeloid differentiation factor 88 (MYD88) and toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta (TRIF) and the downstream effectors TNF-alpha, TNF-alpha/IL-10 ratio and nuclear factor-kappaB (NF-kappaB). It also increased the anti-inflammatory cytokine IL-10 and decreased the activity of the apoptotic marker, caspase-3. These data indicate that limonin exerts antioxidant and anti-inflammatory effects in ischemic liver, thus, protecting hepatocytes against I/R injury in rats. The mechanism of these hepatoprotective effects appears to be related to the antioxidant and anti-inflammatory potential of limonin mediated by the down regulation of TLR- signaling pathway. CI - Copyright (c) 2014 Elsevier B.V. All rights reserved. FAU - Mahmoud, Mona F AU - Mahmoud MF AD - Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. Electronic address: mona_pharmacology@yahoo.com. FAU - Gamal, Samar AU - Gamal S AD - Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. FAU - El-Fayoumi, Hassan M AU - El-Fayoumi HM AD - Department of Pharmacology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. LA - eng PT - Journal Article DEP - 20140623 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Adaptor Proteins, Vesicular Transport) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Antioxidants) RN - 0 (Cytokines) RN - 0 (Limonins) RN - 0 (Myd88 protein, rat) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (NF-kappa B) RN - 0 (Ticam1 protein, rat) RN - 0 (Tlr2 protein, rat) RN - 0 (Tlr4 protein, rat) RN - 0 (Toll-Like Receptor 2) RN - 0 (Toll-Like Receptor 4) RN - 4Y8F71G49Q (Malondialdehyde) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 1.11.1.9 (Glutathione Peroxidase) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.3.2.2 (gamma-Glutamyltransferase) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 3.4.22.- (Casp3 protein, rat) RN - EC 3.4.22.- (Caspase 3) RN - L0F260866S (limonin) SB - IM MH - Adaptor Proteins, Vesicular Transport/genetics MH - Alanine Transaminase/blood MH - Animals MH - *Anti-Inflammatory Agents/pharmacology/therapeutic use MH - *Antioxidants/pharmacology/therapeutic use MH - Aspartate Aminotransferases/blood MH - Caspase 3/metabolism MH - Cytokines/metabolism MH - Glutathione Peroxidase/metabolism MH - L-Lactate Dehydrogenase/blood MH - *Limonins/pharmacology/therapeutic use MH - Liver/drug effects/pathology MH - Liver Diseases/*drug therapy/metabolism/pathology MH - Male MH - Malondialdehyde/metabolism MH - Myeloid Differentiation Factor 88/genetics MH - NF-kappa B/genetics MH - Rats, Wistar MH - Reperfusion Injury/*drug therapy/metabolism/pathology MH - Signal Transduction/drug effects MH - Superoxide Dismutase/metabolism MH - Toll-Like Receptor 2/genetics MH - Toll-Like Receptor 4/genetics MH - gamma-Glutamyltransferase/blood OTO - NOTNLM OT - I/R OT - Limonin OT - Oxidative stress OT - TLR EDAT- 2014/06/27 06:00 MHDA- 2016/02/05 06:00 CRDT- 2014/06/27 06:00 PHST- 2014/03/19 00:00 [received] PHST- 2014/06/06 00:00 [revised] PHST- 2014/06/16 00:00 [accepted] PHST- 2014/06/27 06:00 [entrez] PHST- 2014/06/27 06:00 [pubmed] PHST- 2016/02/05 06:00 [medline] AID - S0014-2999(14)00452-X [pii] AID - 10.1016/j.ejphar.2014.06.010 [doi] PST - ppublish SO - Eur J Pharmacol. 2014 Oct 5;740:676-82. doi: 10.1016/j.ejphar.2014.06.010. Epub 2014 Jun 23.