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Acetaminophen toxicity

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https://www.readbyqxmd.com/read/28330995/hepatic-fcrn-regulates-albumin-homeostasis-and-susceptibility-to-liver-injury
#1
Michal Pyzik, Timo Rath, Timothy T Kuo, Sanda Win, Kristi Baker, Jonathan J Hubbard, Rosa Grenha, Amit Gandhi, Thomas D Krämer, Adam R Mezo, Zachary S Taylor, Kevin McDonnell, Vicki Nienaber, Jan Terje Andersen, Atsushi Mizoguchi, Laurence Blumberg, Shalaka Purohit, Susan D Jones, Greg Christianson, Wayne I Lencer, Inger Sandlie, Neil Kaplowitz, Derry C Roopenian, Richard S Blumberg
The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood...
March 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28291796/the-effect-of-acetaminophen-on-ubiquitin-homeostasis-in-saccharomyces-cerevisiae
#2
Angelina Huseinovic, Jolanda S van Leeuwen, Tibor van Welsem, Iris Stulemeijer, Fred van Leeuwen, Nico P E Vermeulen, Jan M Kooter, J Chris Vos
Acetaminophen (APAP), although considered a safe drug, is one of the major causes of acute liver failure by overdose, and therapeutic chronic use can cause serious health problems. Although the reactive APAP metabolite N-acetyl-p-benzoquinoneimine (NAPQI) is clearly linked to liver toxicity, toxicity of APAP is also found without drug metabolism of APAP to NAPQI. To get more insight into mechanisms of APAP toxicity, a genome-wide screen in Saccharomyces cerevisiae for APAP-resistant deletion strains was performed...
2017: PloS One
https://www.readbyqxmd.com/read/28286920/blockade-of-notch-signaling-promotes-acetaminophen-induced-liver-injury
#3
Longfeng Jiang, Michael Ke, Shi Yue, Wen Xiao, Youde Yan, Xiaozhao Deng, Qi-Long Ying, Jun Li, Bibo Ke
Liver injury after experimental acetaminophen treatment is mediated both by direct hepatocyte injury through a P450-generated toxic metabolite and indirectly by activated liver Kupffer cells and neutrophils. This study was designed to investigate the role of Notch signaling in the regulation of innate immune responses in acetaminophen (APAP)-induced liver injury. Using a mouse model of APAP-induced liver injury, wild-type (WT) and toll-like receptor 4 knockout (TLR4 KO) mice were injected intraperitoneally with APAP or PBS...
March 13, 2017: Immunologic Research
https://www.readbyqxmd.com/read/28255555/procalcitonin-impairs-liver-cell-viability-and-function-in-vitro-a-potential-new-mechanism-of-liver-dysfunction-and-failure-during-sepsis
#4
Martin Sauer, Sandra Doß, Johannes Ehler, Thomas Mencke, Nana-Maria Wagner
Purpose. Liver dysfunction and failure are severe complications of sepsis and result in poor outcome and increased mortality. The underlying pathologic mechanisms of hepatocyte dysfunction and necrosis during sepsis are only incompletely understood. Here, we investigated whether procalcitonin, a biomarker of sepsis, modulates liver cell function and viability. Materials and Methods. Employing a previously characterized and patented biosensor system evaluating hepatocyte toxicity in vitro, human hepatocellular carcinoma cells (HepG2/C3A) were exposed to 0...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28253482/aav-nrf2-promotes-protection-and-recovery-in-animal-models-of-oxidative-stress
#5
Katharine J Liang, Kenton T Woodard, Mark A Weaver, John Paul Gaylor, Ellen R Weiss, R Jude Samulski
NRF2 is a transcription factor that drives antioxidant gene expression in multiple organ systems. We hypothesized that Nrf2 overexpression could be therapeutically applied toward diseases in which redox homeostasis is disrupted. In this study, adeno-associated virus (AAV)-Nrf2 was tested in a mouse model of acute acetaminophen-induced liver toxicity and successfully conferred protection from hepatotoxicity, validating the vector design and early onset of NRF2-mediated protection. Furthermore, therapeutic potential of AAV-Nrf2 in chronic disease also was tested in a light-induced mouse model of age-related macular degeneration...
March 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28246565/diphenhydramine-as-a-cause-of-drug-induced-liver-injury
#6
Yunseok Namn, Yecheskel Schneider, Isabelle H Cui, Arun Jesudian
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status...
2017: Case Reports in Hepatology
https://www.readbyqxmd.com/read/28246450/protective-effect-of-rutin-in-comparison-to-silymarin-against-induced-hepatotoxicity-in-rats
#7
M Kasi Reddy, A Gopala Reddy, B Kala Kumar, D Madhuri, G Boobalan, M Anudeep Reddy
AIM: The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN) in comparison to silymarin (SLM) against acetaminophen (APAP)-induced hepatotoxicity in rats. MATERIALS AND METHODS: Male Wistar albino rats (n=24) of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days...
January 2017: Veterinary World
https://www.readbyqxmd.com/read/28219592/urgent-liver-transplantation-for-dietary-supplements-an-under-recognized-problem
#8
L L Wong, L Lacar, M Roytman, S L Orloff
BACKGROUND: The recent outbreak of acute liver failure caused by herbal/dietary supplements (HDS) in Hawaii prompted evaluation of those patients who underwent emergency liver transplantation (LT) for HDS in the United States. METHODS: We queried the Scientific Registry of Transplant Recipients (2003-2015) to identify patients who underwent urgent LT for acute hepatic necrosis (AHN) and identified those with HDS use. This group of patients was then characterized...
March 2017: Transplantation Proceedings
https://www.readbyqxmd.com/read/28216953/therapeutic-potential-of-alpha-ketoglutarate-against-acetaminophen-induced-hepatotoxicity-in-rats
#9
Lalita Mehra, Yasha Hasija, Gaurav Mittal
OBJECTIVE: Alpha-ketoglutarate (α-KG) is a cellular intermediary metabolite of Krebs cycle, involved in energy metabolism, amino acid synthesis, and nitrogen transport. It is available over-the-counter and marketed as a nutritional supplement. There is a growing body of evidence to suggest that dietary α-KG has the potential to maintain cellular redox status and thus can protect various oxidative stress induced disease states. The aim of the present study was to investigate the hepatoprotective role of α-KG in acetaminophen (APAP) induced toxicity in rats...
October 2016: Journal of Pharmacy & Bioallied Sciences
https://www.readbyqxmd.com/read/28210203/wnt-%C3%AE-catenin-signaling-drives-thioacetamide-mediated-heteroprotection-against-acetaminophen-induced-lethal-liver-injury
#10
Vivekkumar P Dadhania, Bharat Bhushan, Udayan Apte, Harihara M Mehendale
Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively)...
January 2017: Dose-response: a Publication of International Hormesis Society
https://www.readbyqxmd.com/read/28209544/sestrin2-protects-against-acetaminophen-induced-liver-injury
#11
Seung Jung Kim, Kyu Min Kim, Ji Hye Yang, Sam Seok Cho, Sang Kyu Lee, Sae Kwang Ku, Il Je Cho, Sung Hwan Ki
Acetaminophen (APAP) overdose accounts for half of the cases of acute liver failure worldwide. We previously reported that that Sestrin2 (Sesn2) protects against d-galactosamine/lipopolysaccharide-induced acute fulminant liver failure. In this study, we demonstrated that Sesn2 protects APAP-induced liver injury in mice, using a recombinant adenovirus encoding Sesn2 (Ad-Sesn2). First, we found that treatment of mice with toxic levels of APAP significantly reduced Sesn2 expression. Tail-vein injection with Ad-Sesn2 inhibited APAP-induced serum alanine aminotransferase and aspartate aminotransferase levels and markedly reduced hepatocyte degeneration and inflammatory cell infiltration...
February 13, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28208010/circulating-plasma-and-exosomal-micrornas-as-indicators-of-drug-induced-organ-injury-in-rodent-models
#12
Young-Eun Cho, Sang-Hyun Kim, Byung-Heon Lee, Moon-Chang Baek
This study was performed to evaluate whether microRNAs (miRNAs) in circulating exosomes may serve as biomarkers of drug-induced liver, kidney, or muscle-injury. Quantitative PCR analyses were performed to measure the amounts of liver-specific miRNAs (miR-122, miR-192, and miR-155), kidney-specific miR-146a, or muscle-specific miR-206 in plasma and exosomes from mice treated with liver, kidney or muscle toxicants. The levels of liver-specific miRNAs in circulating plasma and exosomes were elevated in acetaminophen-induced liver injury and returned to basal levels by treatment with antioxidant N-acetyl-cysteine...
February 17, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28196650/protective-role-of-p53-in-acetaminophen-hepatotoxicity
#13
Yazhen Huo, Shutao Yin, Mingzhu Yan, Sanda Win, Tin Aung Than, Mariam Aghajan, Hongbo Hu, Neil Kaplowitz
p53 is a tumor suppressor with a pro-death role in many conditions. However, in some contexts, evidence supports a pro-survival function. p53 has been shown to be activated in acetaminophen (APAP) toxicity but the impact of this on toxicity is uncertain. In the present study, we have found that p53 plays a protective role in APAP-induced liver injury. We inhibited p53 using three different approaches in mice, pifithrin-α (PFTα), knockdown of p53 expression with antisense oligonucleotide, and p53 knockout...
February 11, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28169862/quantification-of-acetaminophen-and-its-metabolites-in-plasma-using-uplc-ms-doors-open-to-therapeutic-drug-monitoring-in-special-patient-populations
#14
Robert B Flint, Paola Mian, Bart van der Nagel, Nuria Slijkhuis, Birgit C P Koch
BACKGROUND: Acetaminophen (APAP, paracetamol) is the most commonly used drug for pain and fever in both the United States and Europe and is considered safe when used at registered dosages. Nevertheless, differences between specific populations lead to remarkable changes in exposure to potentially toxic metabolites. Furthermore, extended knowledge is required on metabolite formation after intoxication, to optimize antidote treatment. Therefore, the authors aimed to develop and validate a quick and easy analytical method for simultaneous quantification of APAP, APAP-glucuronide, APAP-sulfate, APAP-cysteine, APAP-glutathione, APAP-mercapturate, and protein-derived APAP-cysteine in human plasma by ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry...
April 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28165728/hepatoprotective-effect-of-%C3%AF-glutathione-in-a-murine-model-of-acetaminophen-induced-liver-toxicity
#15
Swati S More, Jaime Nugent, Ashish P Vartak, Steffan M Nye, Robert Vince
Ψ-Glutathione (ψ-GSH) is an orally bioavailable and metabolism-resistant glutathione analogue that has been shown previously to substitute glutathione in most of its biochemical roles. Described here in its entirety is the preclinical evaluation of ψ-GSH as a rescue agent for acetaminophen (APAP) overdose: an event where time is of essence. By employing a murine model, four scenarios commonly encountered in emergency medicine are reconstructed. ψ-GSH is juxtaposed against N-acetylcysteine (NAC), the sole clinically available drug, in each of the scenarios...
February 16, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28165393/reduced-sharpin-and-lubac-formation-may-contribute-to-ccl%C3%A2-or-acetaminophen-induced-liver-cirrhosis-in-mice
#16
Takeshi Yamamotoya, Yusuke Nakatsu, Yasuka Matsunaga, Toshiaki Fukushima, Hiroki Yamazaki, Sunao Kaneko, Midori Fujishiro, Takako Kikuchi, Akifumi Kushiyama, Fuminori Tokunaga, Tomoichiro Asano, Hideyuki Sakoda
Linear ubiquitin chain assembly complex (LUBAC), composed of SHARPIN (SHANK-associated RH domain-interacting protein), HOIL-1L (longer isoform of heme-oxidized iron-regulatory protein 2 ubiquitin ligase-1), and HOIP (HOIL-1L interacting protein), forms linear ubiquitin on nuclear factor-κB (NF-κB) essential modulator (NEMO) and induces NF-κB pathway activation. SHARPIN expression and LUBAC formation were significantly reduced in the livers of mice 24 h after the injection of either carbon tetrachloride (CCl₄) or acetaminophen (APAP), both of which produced the fulminant hepatitis phenotype...
February 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28159815/validation-of-the-prognostic-utility-of-the-electrocardiogram-for-acute-drug-overdose
#17
Alex F Manini, Ajith P Nair, Rajesh Vedanthan, David Vlahov, Robert S Hoffman
BACKGROUND: While it is certain that some emergency department patients with acute drug overdose suffer adverse cardiovascular events (ACVE), predicting ACVE is difficult. The prognostic utility of the ECG for heterogeneous drug overdose patients remains to be proven. This study was undertaken to validate previously derived features of the initial ECG associated with ACVE in this population. METHODS AND RESULTS: We performed a prospective validation cohort study to evaluate adult emergency department patients with acute drug overdose at 2 urban university hospitals over 5 years in whom an emergency department admission ECG was performed...
February 3, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28153389/gold-nanoparticles-ameliorate-acetaminophen-induced-hepato-renal-injury-in-rats
#18
Mohd Salim Reshi, Sadhana Shrivastava, Amita Jaswal, Neelu Sinha, Chhavi Uthra, Sangeeta Shukla
Valuable effects of gold particles have been reported and used in complementary medicine for decades. The aim of this study was to evaluate the therapeutic efficacy of gold nanoparticles (AuNPs) against acetaminophen (APAP) induced toxicity. Albino rats were administered APAP at a dose of 2g/kg p.o. once only. After 24h of APAP intoxication, animals were treated with three different doses of AuNPs (50μg/kg, 100μg/kg, 150μg/kg) orally or silymarin at a dose of 50mg/kg p.o., once only. Animals of all the groups were sacrificed after 24h of last treatment...
January 30, 2017: Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Für Toxikologische Pathologie
https://www.readbyqxmd.com/read/28152447/astaxanthin-pretreatment-attenuates-acetaminophen-induced-liver-injury-in-mice
#19
Jingyao Zhang, Simin Zhang, Jianbin Bi, Jingxian Gu, Yan Deng, Chang Liu
BACKGROUND: Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure...
January 31, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28130915/multiscale-modeling-reveals-inhibitory-and-stimulatory-effects-of-caffeine-on-acetaminophen-induced-toxicity-in-humans
#20
C Thiel, H Cordes, V Baier, L M Blank, L Kuepfer
Acetaminophen (APAP) is a widely used analgesic drug that is frequently co-administered with caffeine (CAF) in the treatment of pain. It is well known that APAP may cause severe liver injury after an acute overdose. However, the understanding of whether and to what extent CAF inhibits or stimulates APAP-induced hepatotoxicity in humans is still lacking. Here, a multiscale analysis is presented that quantitatively models the pharmacodynamic (PD) response of APAP during co-medication with CAF. Therefore, drug-drug interaction (DDI) processes were integrated into physiologically based pharmacokinetic (PBPK) models at the organism level, whereas drug-specific PD response data were contextualized at the cellular level...
February 2017: CPT: Pharmacometrics & Systems Pharmacology
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