PMID- 31606943 OWN - NLM STAT- MEDLINE DCOM- 20210324 LR - 20211204 IS - 1932-8494 (Electronic) IS - 1932-8486 (Linking) VI - 303 IP - 7 DP - 2020 Jul TI - Perindopril Ameliorates Hepatic Ischemia Reperfusion Injury Via Regulation of NF-kappaB-p65/TLR-4, JAK1/STAT-3, Nrf-2, and PI3K/Akt/mTOR Signaling Pathways. PG - 1935-1949 LID - 10.1002/ar.24292 [doi] AB - Hepatic ischemia reperfusion (IR) is an inevitable clinical problem for surgical procedures such as liver transplantation and liver resection. This study was designed to evaluate the protective effect of perindopril (PER) against hepatic IR injury. Thirty-two rats were used and randomly allocated into four groups. Sham control group was subjected to sham operation and received saline only, IR group was subjected to IR and received vehicle, PER group was pretreated with PER (one milligram per kilogram per day i.p. for 10 consecutive days), and IR+PER group was pretreated with PER then subjected to IR. Liver function biomarkers (aspartate aminotransferase and alanine aminotransferase), oxidative stress (glutathione, malondialdehyde, myeloperoxidase, and superoxide dismutase) and inflammation markers (tumor necrosis factor-alpha, interferon-gamma, and inteleukin-10 [IL-10]), mRNA expression of NF-kappaB-p65 and TLR-4, as well as protein expression of JAK1, STAT-3, PI3K, mTOR, Akt, and Nrf-2 were investigated concomitantly with histopathological examination. The results indicated that, hepatic IR induced a significant alteration in liver function biomarkers and structure, oxidative stress, and inflammation. At the molecular level, up-regulation of NF-kappaB-p65, TLR-4, JAK1, and STAT-3 concomitantly with down-regulation of Nrf-2, IL-10, PI3K, Akt, and mTOR were observed. These disturbances were alleviated by pretreatment of IR rats with PER in concomitant with hepatic structural improvement. Conclusively, the protective effect of PER presumably may be relevant to its ability to reduce oxidative stress, ameliorate the inflammatory processes, and modify the related signaling pathways. Anat Rec, 2019. (c) 2019 American Association for Anatomy Anat Rec, 303:1935-1949, 2020. (c) 2019 American Association for Anatomy. CI - (c) 2019 American Association for Anatomy. FAU - Kamel, Esam O AU - Kamel EO AD - Department of Medical Histology and Cell Biology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt. FAU - Hassanein, Emad H M AU - Hassanein EHM AD - Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt. FAU - Ahmed, Marwa A AU - Ahmed MA AD - Department of Pharmacology, Faculty of Medicine, Assiut University, Asyut, Egypt. FAU - Ali, Fares E M AU - Ali FEM AUID- ORCID: 0000-0001-8341-7458 AD - Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt. LA - eng PT - Journal Article DEP - 20191106 PL - United States TA - Anat Rec (Hoboken) JT - Anatomical record (Hoboken, N.J. : 2007) JID - 101292775 RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Biomarkers) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (Nfe2l2 protein, rat) RN - 0 (STAT3 Transcription Factor) RN - 0 (Toll-Like Receptor 4) RN - EC 2.7.10.2 (Janus Kinase 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - Y5GMK36KGY (Perindopril) SB - IM MH - Angiotensin-Converting Enzyme Inhibitors/*pharmacology/therapeutic use MH - Animals MH - Biomarkers/blood MH - Janus Kinase 1/metabolism MH - Liver/*blood supply/metabolism MH - Male MH - NF-E2-Related Factor 2/metabolism MH - NF-kappa B/metabolism MH - Oxidative Stress/drug effects MH - Perindopril/*pharmacology/therapeutic use MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats MH - Rats, Wistar MH - Reperfusion Injury/*drug therapy/metabolism MH - STAT3 Transcription Factor/metabolism MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/metabolism MH - Toll-Like Receptor 4/metabolism OTO - NOTNLM OT - JAK1/STAT-3 OT - NF-kappaB-p65/TLR-4 OT - PI3K/AKT/mTOR OT - hepatic IR OT - perindopril EDAT- 2019/10/14 06:00 MHDA- 2021/03/25 06:00 CRDT- 2019/10/14 06:00 PHST- 2019/06/23 00:00 [received] PHST- 2019/08/28 00:00 [revised] PHST- 2019/09/03 00:00 [accepted] PHST- 2019/10/14 06:00 [pubmed] PHST- 2021/03/25 06:00 [medline] PHST- 2019/10/14 06:00 [entrez] AID - 10.1002/ar.24292 [doi] PST - ppublish SO - Anat Rec (Hoboken). 2020 Jul;303(7):1935-1949. doi: 10.1002/ar.24292. Epub 2019 Nov 6.