Dataset Information

Diminazene aceturate attenuates hepatic ischemia/reperfusion injury in mice.

ABSTRACT: Hepatic ischemia/reperfusion (I/R) injury is one of the leading causes of mortality following partial hepatectomy, liver transplantation, hypovolemic shock and trauma; however, effective therapeutic targets for the treatment of hepatic I/R injury are lacking. Recent studies have shown that diminazene aceturate (DIZE) has protective effects against inflammation, oxidative stress and cell death, which are the main pathogenetic mechanisms associated with hepatic I/R injury. However, the mechanistic effects DIZE exerts on hepatic I/R remain unknown. C57BL/6 male mice were pretreated with either 15 mg/kg DIZE or vehicle control (saline) and subjected to partial liver ischemia for 60 min. One day after induction of hepatic I/R, liver damage, inflammatory responses, oxidative stress and apoptosis were analyzed. By evaluating plasma alanine aminotransferase levels and histology, we found that DIZE treatment attenuated liver failure and was associated with a reduction in histologically-apparent liver damage. We also found that DIZE-treated mice had milder inflammatory responses, less reactive oxidative damage and less apoptosis following hepatic I/R compared to vehicle-treated mice. Taken together, our study demonstrates that DIZE protects against ischemic liver injury by attenuating inflammation and oxidative damage and may be a potential therapeutic agent for the prevention and treatment of ischemic liver failure.

SUBMITTER: Yoon SH

PROVIDER: S-EPMC9616812 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Diminazene aceturate attenuates hepatic ischemia/reperfusion injury in mice.

Yoon So Hye SH Kang Hye Bin HB Kim Jongwan J Yoo Keunje K Han Sang Jun SJ

Scientific reports 20221028 1

Hepatic ischemia/reperfusion (I/R) injury is one of the leading causes of mortality following partial hepatectomy, liver transplantation, hypovolemic shock and trauma; however, effective therapeutic targets for the treatment of hepatic I/R injury are lacking. Recent studies have shown that diminazene aceturate (DIZE) has protective effects against inflammation, oxidative stress and cell death, which are the main pathogenetic mechanisms associated with hepatic I/R injury. However, the mechanistic ...[more]

PMID: 36307457

Similar Datasets

Project description:Hepatic ischemia/reperfusion (I/R) injury is a major complication after liver transplantation, major hepatic resection, or prolonged portal vein occlusion. Furthermore, acute kidney injury is frequent after hepatic I/R and greatly increases postoperative complications. Sphinganine-1-phosphate is a sphingolipid with uncharacterized physiological effects. We serendipitously determined that plasma levels of sphinganine-1-phosphate fell significantly after liver I/R in mice. In this study, we hypothesized that repletion of plasma sphinganine-1-phosphate would protect against liver and kidney injuries after liver I/R. C57BL/6 mice were subjected to 60 min of partial hepatic I/R and treated with either vehicle or with sphinganine-1-phosphate (given immediately before and 2 h after reperfusion). Vehicle-treated mice subjected to liver I/R developed acute liver and kidney injuries with elevated plasma alanine aminotransferase and creatinine 5 and 24 h after liver I/R. However, liver and kidney injuries were significantly attenuated with sphinganine-1-phosphate treatment. Sphinganine-1-phosphate markedly inhibited liver and kidney necrosis and apoptosis 24 h after liver I/R. Moreover, sphinganine-1-phosphate attenuated neutrophil infiltration, reduced plasma IL-6 and TNF-alpha upregulation, and preserved liver and kidney vascular integrity while reducing liver and kidney F-actin degradation after liver I/R. Finally, sphinganine-1-phosphate-mediated hepatic and renal protection was blocked by VPC23019, an antagonist for sphingosine-1-phosphate type 1 receptor. Therefore, sphinganine-1-phosphate improves acute liver and kidney injuries after hepatic I/R via sphingosine-1-phosphate type 1 receptor-mediated inhibition of necrosis and apoptosis and by improving vascular integrity. Harnessing the mechanisms of cytoprotection with sphinganine-1-phosphate activation may lead to new therapies for perioperative hepatic I/R injury and subsequent remote organ injury.

Project description:BackgroundSevoflurane can protect organs from ischemia-reperfusion (IR) injury, but the mechanism is still unclear. MicroRNA-122 (miR-122) is a liver-specific microRNA (miRNA) and regulates liver function. Therefore, this study aims to elucidate the relationship between the protective effect of sevoflurane and miR-122 in liver IR injury.MethodsWistar rats were divided into the following groups: sham, IR, IR + sevoflurane, IR + miR-122 antagomir, and IR + miR-122 antagomir + sevoflurane. Hematoxylin and eosin (H&E) staining and Suzuki score were used to evaluate the pathological damage of the liver. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 in the serum and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) in the liver homogenate supernatant were detected by using the corresponding kit. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) and flow cytometry was applied to evaluate the apoptosis of liver tissues. The expression of nuclear factor E2-related factor 2 (Nrf2), miR-122, p53, and HO-1 in liver tissue was evaluated by using immunohistochemistry, qRT-PCR, and western blot as needed.ResultsCompared to the IR group, the sevoflurane post-treatment or miR-122 antagomir groups showed improved liver injury, decreased Suzuki score, inhibited the levels of AST, ALT, LDH, MDA, NO, TNF-α, IL-1β, and IL-6, increased levels of SOD, IL-10, and inhibited hepatocyte apoptosis. Regarding the molecular mechanism, sevoflurane post-treatment fostered the expression of HO-1, promoted the transport of Nrf2 from cytoplasm to the nucleus, and decreased the expression of miR-122 and p53. The combined use of miR-122 antagomir and sevoflurane enhanced the protective effect of miR-122 antagomir in liver injury in IR rats.ConclusionsSevoflurane protected the liver from IR damage by regulating the miR-122/Nrf2/HO-1 pathway.

Project description:ObjectiveHepatic ischemia-reperfusion injury (HIRI) frequently occurs as a complication in liver surgeries, which significantly impacting patient outcomes. Sinensetin (SEN) is a plant-derived polymethoxylated flavone with anti-inflammatory and anti-oxidative activities. However, the hepatoprotective effect of sinensetin in HIRI pathogenesis have not been fully explored.MethodsWe constructed the HIRI model in mice, with blood and liver samples collected at 6 and 24 h after reperfusion to evaluate liver injury. We also evaluated the protective effect of sinensetin in mice liver I/R injury through histopathological observation, enzyme activity, immunofluorescence, Western blot, molecular docking, and molecular pharmacology experiments.ResultsIn our study, we have successfully established the mouse HIRI injury model, and the liver function indicators such as ALT, AST and LDH were significantly increased in the HIRI model group, while SEN pretreatment could lead to a significant decrease in these enzymatic activities, especially perfusion at 6 h. In addition, hepatocytic necrosis and lipid deposition were significantly improved under SEN pretreatment conditions compared to the HIRI group alone. Meanwhile, HIRI can significantly increase the expression of genes related to liver injury and inflammation, while SEN pretreatment can lead to a concentration-dependent decrease in these genes. Besides, the level of liver apoptosis and apoptosis-related genes such as BAX and Bcl-2 were significantly reduced especially in the high concentration SEN pretreatment group, and antioxidant enzyme activities such as CAT and GSH-Px also showed similar changes. Moreover, the HIRI model and SEN pretreatment could lead to dynamic changes in key genes involved in endoplasmic reticulum (ER) stress signaling, while the expression and distribution of GRP78 and CHOP proteins in liver cells also showed significant decrease in HIRI + L-SEN and HIRI + H-SEN groups. Molecular docking simulation showed theoretical binding between SEN-GRP78 and SEN-IRE1α in three-dimensional structures. Ultimately, the use of 4-PBA to pharmacologically inhibit ER stress may substantially reduce liver damage caused by HIRI in mice.ConclusionTaken together, our results suggested that sinensetin could alleviate HIRI injury through suppressing GRP78/CHOP-mediated ER stress, which may provide a novel therapeutic strategy for treating liver ischemia-reperfusion injury in clinical practice.

Dataset Information

Diminazene aceturate attenuates hepatic ischemia/reperfusion injury in mice.

Publications

Diminazene aceturate attenuates hepatic ischemia/reperfusion injury in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets