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Nora Freyer, Selina Greuel, Fanny Knöspel, Florian Gerstmann, Lisa Storch, Georg Damm, Daniel Seehofer, Jennifer Foster Harris, Rashi Iyer, Frank Schubert, Katrin Zeilinger
The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP ( p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP ( p < 0...
March 15, 2018: Bioengineering
Prachi Borude, Bharat Bhushan, Udayan Apte
Acetaminophen (APAP) overdose is the leading cause of Acute Liver Failure (ALF) with limited treatment options. It is known that liver regeneration following APAP induced ALF is a deciding factor in the final outcome. Previous studies from our laboratory using incremental dose model involving a regenerating (300 mg/kg, APAP300) and a non-regenerating (600 mg/kg, APAP600) dose of APAP in mice have revealed several pro- regenerative pathways that regulate regeneration after APAP overdose. Here we report that DNA damage and repair mechanisms regulate initiation liver regeneration following APAP overdose...
March 14, 2018: Gene Expression
Shenhai Gong, Tian Lan, Liyan Zeng, Haihua Luo, Xiaoyu Yang, Na Li, Xiaojiao Chen, Zhanguo Liu, Rui Li, Sanda Win, Shuwen Liu, Hongwei Zhou, Bernd Schnabl, Yong Jiang, Neil Kaplowitz, Peng Chen
BACKGROUND & AIMS: Acetaminophen (APAP) induced hepatotoxicity is a leading cause of acute liver failure worldwide. It is well established that the liver damage induced by acetaminophen exhibits diurnal variation. However, the detailed mechanism for the hepatotoxic variation is not clear. Here we aimed to determine the relative contributions of gut microbiota in modulating the diurnal variation of hepatotoxicity induced by APAP. METHODS: Male Balb/C mice were treated with or without antibiotics and orally administrated a single dose of APAP (300 mg/kg) at ZT0 (when the light is on-start of resting period) and ZT12 (when the light is off-start of active period)...
March 7, 2018: Journal of Hepatology
Byung-Woo Lee, Byung-Suk Jeon, Byung-Il Yoon
Thioredoxin-1 (Trx-1) is a potent therapeutic agent against a variety of diseases because of its actions as an antioxidant and regulator of apoptosis. N-acetyl-p-aminophenol (APAP), commonly known as acetaminophen, generates excessive oxidative stress and triggers hepatocyte cell death, exemplified by regulated necrosis. In the present study, we investigated whether APAP-induced liver injury in a mouse model is associated with "necroptosis," and if pretreatment with recombinant Trx-1 prevents the hepatic injury caused by APAP overdose...
March 7, 2018: Journal of Applied Toxicology: JAT
Aysu Hayriye Tezcan, Omur Ozturk, Sefer Ustebay, Yasemen Adali, Hatice Yagmurdur
BACKGROUND: The aim of the present study was to determine the therapeutic effects of medical ozone therapy on acute acetaminophen (APAP)-induced hepatotoxicity which were not clearly demonstrated in prior studies. METHOD: Twenty-four mice were randomly assigned into three equal groups: Group 1 (control), Group 2 (APAP) and Group 3 (APAP +ozone). Hepatotoxicity was induced by APAP given as a single dose of 300 mg/kg intraperitoneally in Groups 2 and 3. Additionally, Group 3 received 20 mcg/0...
November 13, 2017: Pharmacological Reports: PR
Malte Bachmann, Josef Pfeilschifter, Heiko Mühl
Acetaminophen [paracetamol, N -acetyl- p -aminophenol (APAP)]-induced acute liver injury (ALI) not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL)-1 family member IL-18 in experimental APAP-induced ALI...
2018: Frontiers in Immunology
Stefanie Kennon-McGill, Mitchell R McGill
Research on acetaminophen (APAP) toxicity over the last several decades has focused on the pathophysiology of liver injury, but increasing attention is being paid to other known and possible adverse effects. It has been known for decades that APAP causes acute kidney injury, but confusion exists regarding prevalence, and the mechanisms have not been well investigated. More recently, a number of experimental, clinical and epidemiological studies have reported evidence for pulmonary, endocrine, neurological and neurodevelopmental toxicity, but the quality of evidence from those studies varies...
January 15, 2018: Journal of Clinical and Translational Research
Asmita Pant, Anna K Kopeć, Kevin S Baker, Holly Cline-Fedewa, Daniel A Lawrence, James P Luyendyk
Acetaminophen (APAP)-induced liver injury in mice is associated with activation of the coagulation cascade and deposition of fibrin in liver. Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. PAI-1 expression is increased in both experimental APAP-induced liver injury and patients with acute liver failure. Prior studies have shown that PAI-1 prevents intrahepatic hemorrhage and mortality after APAP challenge, but the downstream mechanisms are not clear...
February 16, 2018: American Journal of Pathology
Nutnicha Tantarungsee, Waranurin Yisarakun, Thananya Thongtan, Laddawan Lalert, Sirinapa Srikam, Preecha Reuangwechvorachai, Praewphan Ingruanglert, Supang Maneesri-le Grand
The present study aimed to investigate the effect of APAP treatment on the expression of pro-inflammatory cytokines in the astrocytes. The mouse astrocyte cells (C8-D1A) were treated with APAP at the concentration of 100 μM for 24 h, 16 and 28 days. The expressions of pro-inflammatory cytokines and NF-kB were determined using western blot analysis. Furthermore, the expression and localization of phosphorylation of NF-kB were detected by immunohistochemical and immunofluorescent analysis. The ultrastructure of C8-D1A cells was as well monitored...
February 14, 2018: Neurotoxicity Research
Yuichi Yokoyama, Yoshifumi Sasaki, Natsuko Terasaki, Taku Kawataki, Koji Takekawa, Yumiko Iwase, Toshinobu Shimizu, Seigo Sanoh, Shigeru Ohta
Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity...
February 14, 2018: Biological & Pharmaceutical Bulletin
Taehyun Roh, Umasankar De, Seong Kwang Lim, Min Kook Kim, Seul Min Choi, Duck Soo Lim, Sungpil Yoon, Sam Kacew, Hyung Sik Kim, Byung-Mu Lee
The detoxifying effect of pyridoxine against acetaminophen (APAP)-induced hepatotoxicity was investigated. HepG2 cells were co-treated with APAP and pyridoxine to compare with betaine or methionine for 24 h. LDH, ALT and AST activities were measured to determine direct cells damage in vitro and in vivo. Lipid peroxidation, antioxidant enzymes activity, and glutathione level were measured. Cytochrome c releaseand procaspase-3, cleaved caspase-3, Bcl-2, or Bax protein levels were measured to determine APAP-induced apoptotic cell death...
February 10, 2018: Food and Chemical Toxicology
Xue Wang, Jingran Liu, Xiaohui Zhang, Shimin Zhao, Kai Zou, Jiming Xie, Xinxu Wang, Chunyan Liu, Jinling Wang, Yuzhen Wang
BACKGROUND: Oxidative stress is concomitant with acetaminophen (APAP)-induced hepatotoxicity, which has been highlighted as therapeutic targets for such diseases. The berries of Seabuckthorn (Hippophae rhamnoides L.) have been traditionally used in Tibetan medicine for thousands of years. The effect of Seabuckthorn berry polysaccharide on drug- induced liver injury (DILI) has not yet been elucidated. PURPOSE: This study aims to investigate the protective effects and mechanisms of Seabuckthorn polysaccharide (SP) against APAP-induced hepatotoxicity...
January 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Suellen B Morais, Barbara C Figueiredo, Natan R G Assis, Debora M Alvarenga, Mariana T Q de Magalhães, Rafaela S Ferreira, Angélica T Vieira, Gustavo B Menezes, Sergio C Oliveira
Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-1 serine protease inhibitor in parasite development and as a molecule capable of regulating different models of inflammatory diseases. First, we determine that recombinant (r) SmKI-1 and its Kunitz domain but not the C-terminal region possess inhibitory activity against trypsin and neutrophil elastase (NE). To better understand the molecular basis of NE inhibition by SmKI-1, molecular docking studies were also conducted...
February 9, 2018: PLoS Pathogens
Sergio Montserrat-de la Paz, Maria Dolores Garcia-Gimenez, Ana Maria Quilez, Rocio De la Puerta, Angeles Fernandez-Arche
BACKGROUND: The dried rhizome of ginger has been widely used for more than 2500 years in folk medicine for the treatment of various diseases that involve inflammation or are caused by oxidative stress. AIMS: This study was designed to compare the anti-nociceptive and anti-inflammatory effect of dried powdered ginger rhizome (GR) and paracetamol (APAP) on an experimental mouse model of fibromyalgia syndrome (FMS) induced by intermittent cold stress (ICS). METHODS: Forty-eight female C57BL/6 J mice were used for the experiments...
February 8, 2018: Inflammopharmacology
Mark Yarema, Puja Chopra, Marco L A Sivilotti, David Johnson, Alberto Nettel-Aguirre, Benoit Bailey, Charlemaigne Victorino, Sophie Gosselin, Roy Purssell, Margaret Thompson, Daniel Spyker, Barry Rumack
BACKGROUND: Anaphylactoid reactions to intravenous (IV) N-acetylcysteine (NAC) are well-recognized adverse events during treatment for acetaminophen (APAP) poisoning. Uncertainty exists regarding their incidence, severity, risk factors, and management. We sought to determine the incidence, risk factors, and treatment of anaphylactoid reactions to IV NAC in a large, national cohort of patients admitted to hospital for acetaminophen overdose. METHODS: This retrospective medical record review included all patients initiated on the 21-h IV NAC protocol for acetaminophen poisoning in 34 Canadian hospitals between February 1980 and November 2005...
February 8, 2018: Journal of Medical Toxicology: Official Journal of the American College of Medical Toxicology
Huan Liang, Yang Feng, Ruixia Cui, Minglong Qiu, Jingyao Zhang, Chang Liu
The present study aimed to investigate the effect of simvastatin on acetaminophen (APAP) hepatotoxicity in a mouse model. Male C57BL/6 mice were allocated into the following groups: control, APAP, APAP+SIM10, APAP+SIM20, APAP+SIM100 and APAP+SIM200 groups. The mice in the APAP group were treated with saline intraperitoneally (i.p.) 72 h before and 24 h or 72 h after APAP challenge (i.p., 400 mg/kg of APAP). The simvastatin-treated groups were treated with different doses of simvastatin i.p. (10, 20, 100 and 200 mg/kg/day) as in the APAP group...
February 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Wen-Qi Xia, Ruo-Fei Li, Jia-Bao Liu, Bao-Song Cui, Qi Hou, Hua Sun, Shuai Li
Eleven previously undescribed compounds including two triterpenes, ilexchinenin A and ilexchinenin B, and nine triterpenoid saponins, ilexchinenosides A-I, along with twelve known triterpenoids were isolated from the leaves of Ilex chinensis Sims (Aquifoliaceae). Their structures were elucidated by spectroscopic analysis and comparison with known compounds. Furthermore, eight compounds exhibited significant inhibitory effects on NO production of lipopolysaccharide (LPS)-induced murine macrophages, while nine compounds exhibited potent hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced HepG2 cell damage in in vitro assays...
February 5, 2018: Phytochemistry
Delia Blaya, Beatriz Aguilar-Bravo, Fengjie Hao, Silvia Casacuberta-Serra, Mar Coll, Luis Perea, Júlia Vallverdú, Isabel Graupera, Elisa Pose, Laura Llovet, Jordi Barquinero, Francisco Javier Cubero, Juan Caballería, Pere Ginès, Pau Sancho-Bru
miR-155 is involved in immune and inflammatory diseases and is associated with liver fibrosis and steatohepatitis. However, the mechanisms involved in miR-155 regulation of liver injury are largely unknown. The role of miR-155 in acute liver injury was assessed in wild type (WT), miR-155-/- and miR-155-/- mice transplanted with WT bone marrow. Additionally, miR-155 expression was evaluated in liver tissue and peripheral blood mononuclear cells (PBMC) of patients with autoimmune hepatitis. Concanavalin A (ConA) but not acetaminophen (APAP) treatment increased the expression of miR-155 in liver tissue of WT mice...
February 8, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Peng Cao, Jinlu Sun, Mitchell A Sullivan, Xiao Huang, Hanxiang Wang, Yu Zhang, Na Wang, Kaiping Wang
Acetaminophen (APAP)-induced hepatic damage is prevalent in western countries. The present study aimed to investigate the hepatoprotective effects of Angelica sinensis polysaccharide (ASP), an active constituent derived from a water extract of Angelica sinensis, in rats exposed to an APAP overdose. The mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters including alanine aminotransferase (ALT), aspartate transaminase (AST), glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD) were evaluated, and key proteins involved in hepatic apoptosis, including cleaved caspase-3, Bax and Bcl-2 were quantified...
February 2, 2018: International Journal of Biological Macromolecules
Tsai-Kun Wu, Hsiao-Chun Liu, Shu-Yu Lin, Yung-Luen Yu, Chyou-Wei Wei
Acetaminophen (APAP) is an analgesic and antipyretic agent primarily used in the clinical setting. However, high doses of APAP can cause oxidative stress. Guavas have been reported to provide anti‑inflammatory, anti‑microbial, anti‑oxidative and anti‑diarrheal functions. In addition, guavas have been reported to prevent renal damage due to progression of diabetes mellitus. Therefore, the aim of the present study was to investigate whether guavas can reduce APAP‑induced renal cell damage. In the present study, extracts from guavas were obtained and added to APAP‑treated renal tubular endothelial cells...
January 31, 2018: Molecular Medicine Reports
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