Dataset Information

Aucubin Attenuates Liver Ischemia-Reperfusion Injury by Inhibiting the HMGB1/TLR-4/NF-?B Signaling Pathway, Oxidative Stress, and Apoptosis.

ABSTRACT: Liver ischemia-reperfusion injury (IRI) is a common clinical event with high morbidity in patients undergoing complex liver surgery or having abdominal trauma. Inflammatory and oxidative stress responses are the main contributing factors in liver IRI. The iridoid glucoside aucubin (AU) has good anti-inflammatory and antioxidative effects; however, there are no relevant reports on the protective effect of glucosides on hepatic IRI. The purpose of this study was to determine whether AU pretreatment could prevent liver IRI and to explore the mechanism. Sprague-Dawley rats were randomly divided into five groups. The sham operation and IRI control groups were given intraperitoneal injections of normal saline, while the AU low-dose (AU-L) group, AU medium-dose (AU-M) group, and AU high-dose (AU-H) group were given intraperitoneal injections of AU at doses of 1, 5, and 10 mg/kg/day, respectively. After 10 d, liver IRI (70% liver ischemia for 1 h, reperfusion for 6 h) was surgically established in all groups except the sham group. Our results confirmed that liver injury was significantly aggravated after hepatic ischemia-reperfusion. AU alleviated the increase of transaminase and pathological changes induced by ischemia-reperfusion and improved liver damage. AU could also ameliorate the inflammatory and oxidative stress responses induced by ischemia-reperfusion and reduced expression of high mobility group protein (HMG)B1, receptor for advanced glycation end-products (RAGE), tumor necrosis factor (TNF)-?, interleukin (IL)-1?, and reactive oxygen species (ROS). Moreover, AU reduced ischemia-reperfusion-induced mitochondrial dysfunction and cells apoptosis, increased peroxisome proliferator-activated receptor ? coactivator (PGC)-1? and uncoupling (UCP)2 protein expression, and reduced caspase-3, cleaved caspase-3, and Cytochrome P450 proteins (CYP) expression. To determine expression levels of the Toll-like receptor (TLR)-4/nuclear factor-?B (NF-?B) pathway-related proteins in vitro and in vivo, we also measured TLR-4, myeloid differentiation factor88 (MyD88), NF-?B P65, p-P65, I-kappa-B-alpha (I?B-?), and p-I?B-? levels. The results showed that AU effectively inhibited activation of the TLR-4/NF-?B signaling pathway. In conclusion, we showed for the first time a hepatoprotective effect for AU in liver IRI, which acted by inhibiting the HMGB1/TLR-4/NF-?B signaling pathway, oxidative stress, and apoptosis. Pretreatment with AU may be a promising strategy for preventing liver IRI.

SUBMITTER: Zhang S

PROVIDER: S-EPMC7506056 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Aucubin Attenuates Liver Ischemia-Reperfusion Injury by Inhibiting the HMGB1/TLR-4/NF-κB Signaling Pathway, Oxidative Stress, and Apoptosis.

Zhang Shilong S Feng Zanjie Z Gao Weidong W Duan Yuling Y Fan Guoxin G Geng Xin X Wu Bo B Li Kai K Liu Kangwei K Peng Cijun C

Frontiers in pharmacology 20200908

Liver ischemia-reperfusion injury (IRI) is a common clinical event with high morbidity in patients undergoing complex liver surgery or having abdominal trauma. Inflammatory and oxidative stress responses are the main contributing factors in liver IRI. The iridoid glucoside aucubin (AU) has good anti-inflammatory and antioxidative effects; however, there are no relevant reports on the protective effect of glucosides on hepatic IRI. The purpose of this study was to determine whether AU pretreatmen ...[more]

PMID: 33013386

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Project description:Preconditioning of sevoflurane (Sevo) has been demonstrated to protect the liver from ischemia/reperfusion (I/R) injury. However, it is unknown whether it has hepatoprotective when given at the onset of reperfusion (postconditioning), a protocol with more clinical impact. The present study aimed to explore the hepatoprotective effects of Sevo postconditioning against hepatic IR injury in vivo and in vitro and the possible mechanisms. Using a mouse model of hepatic I/R, Sevo postconditioning significantly improved hepatic injury after reperfusion, as demonstrated by reduced AST, ALT, and LDH serum levels and reduced histologic damage in liver tissues. Furthermore, Sevo postconditioning could suppress the apoptosis, inhibit oxidative stress and inflammatory response in liver tissue of HIRI mice, as well as improve the survival rate of HIRI mice. Through analyzing GSE72314 from the gene expression omnibus (GEO) database, it was demonstrated that microRNA (miR)-142 is downregulated by HIRI, which was reversed by Sevo treatment. Further investigation showed that agomiR-142 injection could enhance the hepatoprotective effects of Sevo postconditioning on I/R injury, while antagomiR-142 reversed these effects in mice. Notably, high mobility group box 1 (HMGB1), an important inflammatory factor, was directly targeted by miR-142 in hepatic cells, and we further found that Sevo could inhibit the expression of HMGB1 through up-regulating miR-142 expression in HIRI mice model. In addition, we found that I/R injury induced the activation of TLR4/NF-κB inflammatory pathway was partially suppressed by Sevo postconditioning, and miR-142 mediated the regulatory role of Sevo postconditioning. In line with the in vivo results, Sevo treatment improved the cell viability, inhibited cell apoptosis, oxidative stress and inflammatory response in vitro HIRI model, while these effects were reversed by antagomiR-142 transfection. Collectively, our findings demonstrated that Sevo postconditioning counteracts the downregulation of miR-142 provoked by I/R, in turn decreased the expression of HMGB1, blocking TLR4/NF-κB pathway activation, thus improving hepatic I/R injury. Our data suggest that Sevo may be a valuable alternative anaesthetic agent in liver transplantation and major liver surgeries.

Project description:Ischemic stroke is a clinically common cerebrovascular disease whose main risks include necrosis, apoptosis and cerebral infarction, all caused by cerebral ischemia and reperfusion (I/R) injury. This process has particular significance for the treatment of stroke patients. Notoginseng leaf triterpenes (PNGL), as a valuable medicine, have been discovered to have neuroprotective effects. However, it was not confirmed that whether PNGL may possess neuroprotective effects against cerebral I/R injury. To explore the neuroprotective effects of PNGL and their underlying mechanisms, a middle cerebral artery occlusion/reperfusion (MCAO/R) model was established. In vivo results suggested that in MCAO/R model rats, PNGL pretreatment (73.0, 146, 292 mg/kg) remarkably decreased infarct volume, reduced brain water content, and improved neurological functions; moreover, PNGL (73.0, 146, 292 mg/kg) significantly alleviated blood-brain barrier (BBB) disruption and inhibited neuronal apoptosis and neuronal loss caused by cerebral I/R injury, while PNGL with a different concertation (146, 292 mg/kg) significantly reduced the concentrations of IL-6, TNF-α, IL-1 β, and HMGB1 in serums in a dose-dependent way, which indicated that inflammation inhibition could be involved in the neuroprotective effects of PNGL. The immunofluorescence and western blot analysis showed PNGL decreased HMGB1 expression, suppressed the HMGB1-triggered inflammation, and inhibited microglia activation (IBA1) in hippocampus and cortex, thus dose-dependently downregulating inflammatory cytokines including VCAM-1, MMP-9, MMP-2, and ICAM-1 concentrations in ischemic brains. Interestingly, PNGL administration (146 mg/kg) significantly downregulated the levels of p-P44/42, p-JNK1/2 and p-P38 MAPK, and also inhibited expressions of the total NF-κB and phosphorylated NF-κB in ischemic brains, which was the downstream pathway triggered by HMGB1. All of these results indicated that the protective effects of PNGL against cerebral I/R injury could be associated with inhibiting HMGB1-triggered inflammation, suppressing the activation of MAPKs and NF-κB, and thus improved cerebral I/R-induced neuropathological changes. This study may offer insight into discovering new active compounds for the treatment of ischemic stroke.

Dataset Information

Aucubin Attenuates Liver Ischemia-Reperfusion Injury by Inhibiting the HMGB1/TLR-4/NF-?B Signaling Pathway, Oxidative Stress, and Apoptosis.

Publications

Aucubin Attenuates Liver Ischemia-Reperfusion Injury by Inhibiting the HMGB1/TLR-4/NF-κB Signaling Pathway, Oxidative Stress, and Apoptosis.

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