Scavenger receptor A ameliorates acetaminophen induced hepatic inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221747 | GEO | 2023/12/23
REPOSITORIES: GEO
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Project description:Acetaminophen (APAP) is the major cause of drug-induced liver injury, with limited treatment options. APAP overdose invokes excessive oxidative stress that triggers mitochondria-to-nucleus retrograde pathways, contributing to APAP-induced liver injury (AILI). Mesenchymal stem cell therapy is a promising tool for acute liver failure. Therefore, the purpose of this study is to investigate the beneficial effects of adipose-derived mesenchymal stem cell (AMSC) therapy on AILI and reveal the potential therapeutic mechanisms. C57BL/6 mice are used as the animal model and AML12 normal murine hepatocytes as the cellular model of APAP overdose. Immunohistochemical staining, western blotting, immunofluorescence staining, and RNA sequencing assay are used for assessing the efficacy and validating mechanisms of AMSC therapy. We found AMSC therapy effectively ameliorated AILI, while delayed AMSC injection lost its efficacy related to the c-Jun N-terminal kinase (JNK)-mediated mitochondrial retrograde pathways. We further found that AMSC therapy inhibited JNK activation and mitochondrial translocation, reducing APAP-induced mitochondrial damage. The down-regulation of activated Ataxia telangiectasia mutated (ATM) and DNA damage response proteins in AMSC treated mice liver indicated AMSC blocked the JNK-ATM pathway. Overall, AMSC may be an effective treatment for AILI by inhibiting JNK-ATM mitochondrial retrograde pathway, which improves APAP-induced mitochondrial dysfunction and liver injury.
2022-12-17 | GSE218879 | GEO
Project description:The role of non-parenchymal cells (NPCs) in the early phase of acetaminophen (APAP)-induced liver injury (AILI) remains unclear. Therefore, single-cell sequencing (scRNA-seq) was performed to explore the heterogeneity and immune network of NPCs in the livers of mice with AILI. Mice were challenged with saline, 300 mg/kg APAP, or 750 mg/kg APAP (n=3 for each group). After 3 h, the liver samples were collected, digested, and subjected to scRNA-seq. Immunohistochemistry and immunofluorescence were performed to confirm the expression of Makorin ring finger protein 1 (Mkrn1). We identified 14 distinct cell subtypes among the 120,599 cells. A variety of NPCs were involved even in the early stages of AILI, indicating highly heterogeneous transcriptome dynamics. Cholangiocyte cluster 3 with high Deleted in malignant brain tumors 1 (Dmbt1) expression was found to perform drug metabolism and detoxification functions. Liver sinusoidal endothelial cells displayed fenestrae loss and angiogenesis. Macrophage cluster 1 displayed an M1 polarization phenotype, whereas cluster 3 tended to exhibit M2 polarization. Kupffer cells (KCs) particularly highly expressed Cxcl2 exhibiting pro-inflammatory effects. qRT-PCR and western blotting verified that LIFR-OSM axis might promote the activation of MAPK signaling pathway in RAW264.7 macrophages. Mkrn1 was highly expressed in the liver macrophages of AILI mice and patients with AILI. Interaction patterns between macrophages/KCs and other NPCs were complex and diverse. NPCs were highly heterogeneous and involved in the immune network in the early phase of AILI. In addition, we proposed that Mkrn1 may serve as a potential biomarker of AILI.
2023-09-30 | GSE228305 | GEO
Project description:Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the PXR S-nitrosylation (SNO) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass-spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for SNO-modification. In hepatocytes, SNO suppressed both agonist (rifampicin and SR12813)-induced and constitutively active PXR (VP-PXR) activations. Furthermore, in acetaminophen overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-deficient (PXR-/-) mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis and apoptosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of PXR S-nitrosylation. In conclusion, PXR is post-translationally modified by S-nitrosylation in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a new target for therapeutical intervention.
2024-03-06 | GSE243679 | GEO
Project description:Acetaminophen (APAP) is one of the most widely consumed and prescribed drugs. APAP overdose is one of the leading causes of intrinsic drug-induced liver injury (DILI), acute liver failure (ALF), and liver transplantation in the Western world. Mg2+, essential for health, plays a role in virtually every process within the human cell. The cellular transporter family cyclin M, also known as CNNM, plays a key role in Mg2+ transport across the cell membranes in different organs. Here, we identified that the expression of CNNM4 is elevated in the liver of patients with APAP-induced liver injury (AILI), with a concomitant disturbance in serum Mg2+ levels. We demonstrated that, in the liver, APAP interferes with the Mg2+ mitochondrial reservoir via CNNM4, which affects ATP production and ROS generation, further boosting endoplasmic reticulum (ER) stress of the hepatocytes. Importantly, the CNNM4 mutant T495I showed no effect. Finally, a shift in localization of CNNM4 from membrane to ER was shown under APAP toxicity. Therapeutic targeting of Cnnm4 in the liver with nanoparticles and GalNAc-formulated siRNA provides efficient protection from AILI by restoring hepatocyte Mg2+ homeostasis and by inducing hepatocyte restoration. Our results suggest that inhibition of Cnnm4 may represent an alternative route for the treatment of DILI..
2023-03-11 | PXD036682 | Pride
Project description:Acetaminophen (APAP) overdose provokes various degrees of liver injury, whose pathogenesis involves multiple pathological events, such as mitochondrial damage and necrosis. E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-1 (NEDD4-1) plays vital roles in regulating a wide spectrum of physiological processes, and has been implicated in the pathogenesis of numerous liver disease. However, studies about the regulation of NEDD4-1 on APAP-induced liver injury (AILI) is still deficient. Thus, the aim of this study is to determine whether and how NEDD4-1 plays a role in AILI. Thus, we performed transcriptomic studies comparing liver samples of APAP-treated Flox or APAP-treated hepatocyte-specific Nedd4-1 (HepKO) deficiency mice,
2022-03-29 | GSE199353 | GEO
Project description:Monocyte-derived macrophages play a pivotal role in the resolution of Acetaminophen-Induced Liver Injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necro-inflammatory and resolution phases of AILI. We utilized MC-21 anti mouse CCR2 to induce the ablation of circulating Ly6Chi monocytes. RNA sequencing-based profiling of neutrophils from Ly6Chi monocyte-deficient(MC-21 treated mice) versus normal livers (PBS-treated mice) revealed 449 genes that were differentially expressed with at least two-fold change (p ≤ 0.05). Nutrophils from monocyte-ablated livers exhibited decreased expression of NADPH Oxidase 2. Moreover, in the absence of Ly6Chi monocytes, neutrophils exhibited an altered transcriptomic profile associated with reduced innate activity concomitantly with increased cell survival.Collectively, our findings reveal that liver-infiltrating Ly6Chi monocytes regulating neutrophil activity and survival following AILI.
2017-06-01 | GSE95182 | GEO
Project description:Differential gene expression in mice liver after carbon tetrachloride and acetaminophen administration. Livers from control mice were compared with drug treated mice livers at different time points. Keywords: Time-course
2007-02-27 | GSE4874 | GEO
Project description:Drug Induced-liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. APAP overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Herein, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from APAP-induced liver injury (AILI) patients and in mice treated with an APAP overdose. MLN4924, an inhibitor of the NEDD8 activating enzyme (NAE-1), ameliorated necrosis and boost liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 (bioNEDD8) and Ubiquitin (bioUB) transgenic mice were investigated under APAP overdose with and without MLN4924. The CDP-DAG synthase TAM41, responsible to produce cardiolipin essential for mitochondrial activity, was found modulated under AILI and restoring its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.
2024-06-18 | PXD053221 |
Project description:Purpose: This study investigated the protective effect and further elucidated the mechanisms of action of O. elatus on acetaminophen (APAP)-induced liver injury (AILI). Methods: O. elatus chlorogenic-enriched fraction (OEB) was administrated orally daily for seven consecutive days, followed by a single intraperitoneal injection of an overdose of APAP after the final OEB administration. Results: OEB decreased alanine aminotransferase, aspartate aminotransferase, total cholesterol, total triglycerides contents, regulated superoxide dismutase, catalase, glutathione, malondialdehyde levels, and affected the metabolism of APAP. Furthermore, OEB treatment regulated lipid metabolism, activated the peroxisome proliferator-activated receptors signaling pathway in mice with AILI, affected immune cells, and decreased neutrophil infiltration. Conclusions: This study indicated that OEB is a potential drug candidate for the prevention of APAP-induced hepatotoxicity and elucidated a potential protective mechanism by OEB.
2021-08-20 | GSE182399 | GEO
Project description:Differential gene expression in mice liver after carbon tetrachloride and acetaminophen administration. Livers from control mice were compared with drug treated mice livers at different time points. Keywords: Time-course Mice (Mus musculus) belonging to control and carbon tetrachloride and acetaminophen-administered groups (n=4) were sacrificed. The livers were snap frozen in liquid nitrogen, and subsequently stored at -80ºC till further use. Liver samples were homogenized and total RNA was extracted with TRI reagent. 25 ug of total RNA was converted into labeled cDNA using CyScribe first strand cDNA labeling kit. The Cy5 and Cy3 labeled cDNAs were resuspended in Cyscribe Hyb buffer containing 10ug/ml sheared Salmon sperm DNA and 10ug/ml Yeast tRNA. The labeled samples were hybridized to the arrays and incubated for 16-18hrs at 42ºC. Fluorescent array images were collected for both Cy3 and Cy5 with molecular dynamics III scanner supported with ImageQuant v5.0. Image intensity data were extracted and analyzed with ArrayVision v8.0 analysis software. Background corrected data was LOWESS normalized and log ratios were calculated using Avadis v4. Further, mean log ratios were calculated for duplicate spots. Replicate experiments were carried out in dye swap manner for each time point.
2010-06-11 | E-GEOD-4874 | biostudies-arrayexpress