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https://www.readbyqxmd.com/read/28225807/increased-liver-specific-proteins-in-circulating-extracellular-vesicles-as-potential-biomarkers-for-drug-and-alcohol-induced-liver-injury
#1
Young-Eun Cho, Eun-Ju Im, Pyong-Gon Moon, Esteban Mezey, Byoung-Joon Song, Moon-Chang Baek
Drug- and alcohol-induced liver injury are a leading cause of liver failure and transplantation. Emerging evidence suggests that extracellular vesicles (EVs) are a source of biomarkers because they contain unique proteins reflecting the identity and tissue-specific origin of the EV proteins. This study aimed to determine whether potentially hepatotoxic agents, such as acetaminophen (APAP) and binge alcohol, can increase the amounts of circulating EVs and evaluate liver-specific EV proteins as potential biomarkers for liver injury...
2017: PloS One
https://www.readbyqxmd.com/read/28219698/protective-effects-of-diallyl-disulfide-against-acetaminophen-induced-nephrotoxicity-a-possible-role-of-cyp2e1-and-nf-%C3%AE%C2%BAb
#2
Je-Won Ko, Jin-Young Shin, Jeong-Won Kim, Sung-Hyeuk Park, Na-Rae Shin, In-Chul Lee, In-Sik Shin, Changjong Moon, Sung-Ho Kim, Sung-Hwan Kim, Jong-Choon Kim
Diallyl disulfide (DADS) is a degradation product of allicin which is contained in garlic. This study investigated the protective effects of DADS against acetaminophen (AAP)-induced nephrotoxicity and the molecular mechanisms of nephroprotective effects in rats. AAP caused severe nephrotoxicity as evidenced by significant increases in renal tubular cell apoptosis, mitochondria-mediated apoptosis, and up-regulation of nuclear transcription factor kappa-B (NF-κB), cyclooxygenase-2 (Cox-2), and tumor necrosis factor-α (TNF-α) in the kidney with histopathological alterations...
February 17, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28219592/urgent-liver-transplantation-for-dietary-supplements-an-under-recognized-problem
#3
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
#4
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
#5
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
#6
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
#7
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/28205631/immature-mice-are-more-susceptible-than-adult-mice-to-acetaminophen-induced-acute-liver-injury
#8
Yan Lu, Cheng Zhang, Yuan-Hua Chen, Hua Wang, Zhi-Hui Zhang, Xi Chen, De-Xiang Xu
Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28205121/effect-of-n-acetylcysteine-on-mortality-and-liver-transplantation-rate-in-non-acetaminophen-induced-acute-liver-failure-a-multicenter-study
#9
Samar K Darweesh, Mona F Ibrahim, Mahmoud A El-Tahawy
INTRODUCTION AND AIM: Previous studies and systematic reviews have not provided conclusive evidence on the effect of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). We aimed to study the value of intravenous NAC in reducing liver transplantation and mortality in NAI-ALF. PATIENTS AND METHODS: In a prospective, multicenter, observational study, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were enrolled...
February 15, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/28196650/protective-role-of-p53-in-acetaminophen-hepatotoxicity
#10
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/28194962/high-speed-quantitative-uplc-ms-analysis-of-multiple-amines-in-human-plasma-and-serum-via-precolumn-derivatization-with-6-aminoquinolyl-n-hydroxysuccinimidyl-carbamate-application-to-acetaminophen-induced-liver-failure
#11
Nicola Gray, Rabiya Zia, Adam King, Vishal C Patel, Julia Wendon, Mark J W McPhail, Muireann Coen, Robert S Plumb, Ian D Wilson, Jeremy K Nicholson
A targeted reversed-phase gradient UPLC-MS/MS assay has been developed for the quantification /monitoring of 66 amino acids and amino-containing compounds in human plasma and serum using precolumn derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQTag Ultra). Derivatization of the target amines required minimal sample preparation and resulted in analytes with excellent chromatographic and mass spectrometric detection properties. The resulting method, which requires only 10 μL of sample, provides the reproducible and robust separation of 66 analytes in 7...
February 7, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28165728/hepatoprotective-effect-of-%C3%AF-glutathione-in-a-murine-model-of-acetaminophen-induced-liver-toxicity
#12
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
#13
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/28153389/gold-nanoparticles-ameliorate-acetaminophen-induced-hepato-renal-injury-in-rats
#14
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
#15
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/28134251/low-dose-acetaminophen-induces-early-disruption-of-cell-cell-tight-junctions-in-human-hepatic-cells-and-mouse-liver
#16
Wesam Gamal, Philipp Treskes, Kay Samuel, Gareth J Sullivan, Richard Siller, Vlastimil Srsen, Katie Morgan, Anna Bryans, Ada Kozlowska, Andreas Koulovasilopoulos, Ian Underwood, Stewart Smith, Jorge Del-Pozo, Sharon Moss, Alexandra Inés Thompson, Neil C Henderson, Peter C Hayes, John N Plevris, Pierre-Olivier Bagnaninchi, Leonard J Nelson
Dysfunction of cell-cell tight junction (TJ) adhesions is a major feature in the pathogenesis of various diseases. Liver TJs preserve cellular polarity by delimiting functional bile-canalicular structures, forming the blood-biliary barrier. In acetaminophen-hepatotoxicity, the mechanism by which tissue cohesion and polarity are affected remains unclear. Here, we demonstrate that acetaminophen, even at low-dose, disrupts the integrity of TJ and cell-matrix adhesions, with indicators of cellular stress with liver injury in the human hepatic HepaRG cell line, and primary hepatocytes...
January 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28130915/multiscale-modeling-reveals-inhibitory-and-stimulatory-effects-of-caffeine-on-acetaminophen-induced-toxicity-in-humans
#17
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...
January 28, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/28123000/dual-role-of-epidermal-growth-factor-receptor-in-liver-injury-and-regeneration-after-acetaminophen-overdose-in-mice
#18
Bharat Bhushan, Hemantkumar Chavan, Prachi Borude, Yuchao Xie, Kuo Du, Mitchell R McGill, Margitta Lebofsky, Hartmut Jaeschke, Partha Krishnamurthy, Udayan Apte
Epidermal growth factor receptor (EGFR) plays a crucial role in hepatocyte proliferation. Its role in acetaminophen (APAP)-mediated hepatotoxicity and subsequent liver regeneration is completely unknown. Role of EGFR after APAP-overdose in mice was studied using pharmacological inhibition strategy. Rapid, sustained and dose-dependent activation of EGFR was noted after APAP-treatment in mice, which was triggered by glutathione depletion. EGFR-activation was also observed in primary human hepatocytes after APAP-treatment, preceding elevation of toxicity markers...
February 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28120901/patient-specific-hepatocyte-like-cells-derived-from-induced-pluripotent-stem-cells-model-pazopanib-mediated-hepatotoxicity
#19
Yukti Choudhury, Yi Chin Toh, Jiangwa Xing, Yinghua Qu, Jonathan Poh, Li Huan, Hui Shan Tan, Ravindran Kanesvaran, Hanry Yu, Min-Han Tan
Idiosyncratic drug-induced hepatotoxicity is a major cause of liver damage and drug pipeline failure, and is difficult to study as patient-specific features are not readily incorporated in traditional hepatotoxicity testing approaches using population pooled cell sources. Here we demonstrate the use of patient-specific hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells for modeling idiosyncratic hepatotoxicity to pazopanib (PZ), a tyrosine kinase inhibitor drug associated with significant hepatotoxicity of unknown mechanistic basis...
January 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28115551/early-detection-of-acute-drug-induced-liver-injury-in-mice-by-non-invasive-nir-fluorescence-imaging
#20
Kristine O Vasquez, Jeffrey D Peterson
Hepatocellular and cholestatic forms of drug induced liver injury (DILI) are major reasons for late stage termination of small molecule drug discovery research projects. Biochemical serum markers are limited in their ability to sensitively and specifically detect both of these common DILI forms in preclinical models, and tissue-specific approaches to assessing this are labor intensive, requiring extensive animal dosing, tissue preparation, and pathology assessment. In vivo fluorescent imaging offers non-invasive detection of biological changes detected directly in the livers of living animals...
January 23, 2017: Journal of Pharmacology and Experimental Therapeutics
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