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Anticholestatic Effect of Bardoxolone Methyl on Hepatic Ischemia-reperfusion Injury in Rats.

ABSTRACT: Background:Cholestasis is a sign of hepatic ischemia-reperfusion injury (IRI), which is caused by the dysfunction of hepatocyte membrane transporters (HMTs). As transcriptional regulation of HMTs during oxidative stress is mediated by nuclear factor erythroid 2-related factor 2, we hypothesized that bardoxolone methyl (BARD), a nuclear factor erythroid 2-related factor 2 activator, can mitigate cholestasis associated with hepatic IRI. Methods:BARD (2 mg/kg) or the vehicle was intravenously administered into rats immediately before sham surgery, 60 min of ischemia (IR60), or 90 min of ischemia (IR90); tissue and blood samples were collected after 24 h to determine the effect on key surrogate markers of bile metabolism and expression of HMT genes (Mrp (multidrug resistance-associated protein) 2, bile salt export pump, Mrp3, sodium-taurocholate cotransporter, and organic anion-transporting polypeptide 1). Results:Significantly decreased serum bile acids were detected upon BARD administration in the IR60 group but not in the IR90 group. Hepatic tissue analyses revealed that BARD administration increased mRNA levels of Mrp2 and Mrp3 in the IR60 group, and it decreased those of bile salt export pump in the IR90 group. Protein levels of multidrug resistance-associated protein 2, multidrug resistance-associated protein 3, and sodium-taurocholate cotransporter were higher in the IR90 group relative to those in the sham or IR60 groups, wherein the difference was notable only when BARD was administered. Immunohistochemical and morphometric analyses showed that the area of expression for multidrug resistance-associated protein 2 and for sodium-taurocholate cotransporter was larger in the viable tissues than in the necrotic area, and the area for multidrug resistance-associated protein 3 was smaller; these differences were notable upon BARD administration. Conclusions:BARD may have the potential to change HMT regulation to mitigate cholestasis in hepatic IRI.

SUBMITTER: Kim J

PROVIDER: S-EPMC7371100 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Anticholestatic Effect of Bardoxolone Methyl on Hepatic Ischemia-reperfusion Injury in Rats.

Kim Joohyun J Hagen Catherine E CE Kumar Suresh N SN Park Jong-In JI Zimmerman Michael A MA Hong Johnny C JC

Transplantation direct 20200717 8

<h4>Background</h4>Cholestasis is a sign of hepatic ischemia-reperfusion injury (IRI), which is caused by the dysfunction of hepatocyte membrane transporters (HMTs). As transcriptional regulation of HMTs during oxidative stress is mediated by nuclear factor erythroid 2-related factor 2, we hypothesized that bardoxolone methyl (BARD), a nuclear factor erythroid 2-related factor 2 activator, can mitigate cholestasis associated with hepatic IRI.<h4>Methods</h4>BARD (2 mg/kg) or the vehicle was intr ...[more]

PMID: 32766432

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Project description:BackgroundD-carvone is a monoterpene that exists in the essential oils of several plant species. Hepatic ischemia-reperfusion (Hep I/R) takes place clinically during different scenarios of liver pathologies. The aim of the current investigation is to disclose the hepato-protective actions of carvone against Hep I/R-induced damage and to reveal the underlying mechanism.Material and methodsRats were assigned into five groups: sham and carvone plus sham groups, in which rats were administered either saline or carvone orally for three weeks prior to the induction of Hep I/R. In the Hep I/R group, rats were administered saline orally prior to the Hep I/R induction operation. The carvone 25 plus Hep I/R and Carvone 50 plus Hep I/R groups were administered carvone (25 and 50 mg/kg, respectively) for three weeks, followed by the induction of Hep I/R.ResultsLiver ischemic animals demonstrated impaired liver function, several histopathological variations, and reduced levels of antioxidant enzyme activities. Furthermore, the Hep I/R groups showed the elevated gene expression of high-mobility group box 1 (HMGB1), toll-like receptors 4 (TLR4), nuclear factor kappa B (NFκB), and LR family pyrin domain containing 3 (NLP3), with subsequent escalated adhesion molecule 1 (ICAM-1), neutrophil infiltration, and several inflammatory mediators, including interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), as well as apoptotic markers. Pretreatment with D-carvone alleviated ischemia/reperfusion-induced impaired liver function, diminished the histopathological deviations, and augmented the antioxidant enzymes. In addition, D-carvone mitigated the gene expression of HMGB1, TLR4, NFκB, and NLP3, with a subsequent reduction in ICAM-1, neutrophils infiltration, inflammatory mediators, and apoptotic markers.ConclusionRats pretreated with D-carvone exhibited hepato-protective actions against Hep I/R-induced damage via the downregulation of HMGB1, TLR4, NFκB, NLP3, associated inflammatory mediators, and apoptotic markers.

Dataset Information

Anticholestatic Effect of Bardoxolone Methyl on Hepatic Ischemia-reperfusion Injury in Rats.

Publications

Anticholestatic Effect of Bardoxolone Methyl on Hepatic Ischemia-reperfusion Injury in Rats.

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