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Effect of Liposomal Curcumin on Acetaminophen Hepatotoxicity by Down-regulation of Oxidative Stress and Matrix Metalloproteinases.

ABSTRACT: BACKGROUND/AIM:The hepatoprotective role of various molecules in drug-induced hepatotoxicity arouses great interest. We investigated the effect of liposomal curcumin (LCC) on experimental acetaminophen (APAP)-induced hepatotoxicity. MATERIALS AND METHODS:Rats were randomly allocated into 5 groups, and the effect of two LCC concentrations was studied: group 1 - 1 ml intraperitoneal (i.p.) saline, group 2 - APAP pretreatment, group 3 - APAP+silymarin (extract of the silybum marianum with anti-inflammatory, anti-oxidant, and anti-fibrotic properties), group 4 - APAP+LCC1, group 5 - APAP+LCC2. The biomarkers of oxidative stress (nitric oxide and malondialdehyde) and antioxidant status of plasma (thiols and catalase), TNF-?, MMP-2 and MMP-9 serum levels were evaluated. RESULTS:An improvement in oxidative stress, antioxidant status, and TNF-?, MMP-2 and MMP-9 levels was obtained in groups pretreated with LCC compared to silymarin treatment, in a dose-dependent manner. Histopathological examination reinforced the results. CONCLUSION:Liposomal curcumin improves the oxidative stress/antioxidant balance and alleviates inflammation in experimental APAP-induced hepatotoxicity.

SUBMITTER: Dogaru G

PROVIDER: S-EPMC7157894 | biostudies-literature | 2020 Mar-Apr

REPOSITORIES: biostudies-literature

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Effect of Liposomal Curcumin on Acetaminophen Hepatotoxicity by Down-regulation of Oxidative Stress and Matrix Metalloproteinases.

Dogaru Gabriela G Bulboaca Adriana Elena AE Gheban Dan D Boarescu Paul Mihai PM Rus Vasile V Festila Dana D Sitar-Taut Adela-Viviana AV Stanescu Ioana I

In vivo (Athens, Greece) 20200301 2

<h4>Background/aim</h4>The hepatoprotective role of various molecules in drug-induced hepatotoxicity arouses great interest. We investigated the effect of liposomal curcumin (LCC) on experimental acetaminophen (APAP)-induced hepatotoxicity.<h4>Materials and methods</h4>Rats were randomly allocated into 5 groups, and the effect of two LCC concentrations was studied: group 1 - 1 ml intraperitoneal (i.p.) saline, group 2 - APAP pretreatment, group 3 - APAP+silymarin (extract of the silybum marianum ...[more]

PMID: 32111755

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Project description:Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

Project description:The glycocalyx is crucial for normal endothelial function. It also tethers extracellular superoxide dismutase (SOD3), which protects the endothelium against oxidative damage. Proteolytic enzymes [matrix metalloproteinases (MMPs)] are capable of disrupting endothelial cell surface proteins, such as syndecans, resulting in derangements of the endothelial glycocalyx. We sought to test the role of MMPs in oxidative stress-mediated disruption of the endothelial glycocalyx and examine the effect of pharmacological inhibition of MMPs on mitigating this detrimental effect. We also examined the role of histone deacetylase (HDAC) in the oxidative stress-mediated MMP induction and glycocalyx remodeling. Oxidative stress was experimentally induced in human adipose microvascular endothelial cells using H2O2 and buthionine sulfoximine in the presence and absence of potent MMP and HDAC inhibitors. H2O2 and buthionine sulfoximine resulted in a notable loss of the endothelial glycocalyx; they also increased the expression and proteolytic activity of MMP-2 and MMP-9 and subsequently increased the shedding of syndecan-1 and SOD3 from the endothelial cell surface. MMP upregulation was accompanied by a decline in mRNA and protein levels of their inhibitors, tissue inhibitors of metalloproteinase (TIMPs; TIMP-1 and TIMP-3). Furthermore, oxidative stress induced HDAC activity. Inhibition of MMPs and HDAC reversed syndecan-1 and SOD3 shedding and maintained endothelial glycocalyx integrity. HDAC inhibition increased TIMP expression and reduced MMP expression and activity in endothelial cells. Our findings shed light on MMPs and HDAC as therapeutically targetable mechanisms in oxidative stress-induced glycocalyx remodeling. NEW & NOTEWORTHY Oxidative stress, a hallmark of many diseases, damages the endothelial glycocalyx, resulting in vascular dysfunction. Studying the mechanistic link between oxidative stress and endothelial glycocalyx derangements might help discover new therapeutic targets to preserve vascular function. In this study, we investigated the involvement of matrix metalloproteinases and histone deacetylase in oxidative stress-induced endothelial glycocalyx degradation.

Dataset Information

Effect of Liposomal Curcumin on Acetaminophen Hepatotoxicity by Down-regulation of Oxidative Stress and Matrix Metalloproteinases.

Publications

Effect of Liposomal Curcumin on Acetaminophen Hepatotoxicity by Down-regulation of Oxidative Stress and Matrix Metalloproteinases.

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