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A D B Vliegenthart, R A Kimmitt, J H Seymour, N Z Homer, J I Clarke, M Eddleston, A Gray, D M Wood, P I Dargan, J G Cooper, D J Antoine, D J Webb, S C Lewis, D N Bateman, J W Dear
: Acetaminophen (paracetamol-APAP) is the commonest cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analysed from discovery (N=116) and validation (N=150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI...
October 22, 2016: Clinical Pharmacology and Therapeutics
Sarsvat Patel, Xiang Kou, Hao Helen Hou, Ye Bill Huang, John C Strong, Geoff G Z Zhang, Changquan Calvin Sun
Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (Tg) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content...
October 18, 2016: Journal of Pharmaceutical Sciences
Matthijs T W Veltmeijer, Dineke Veeneman, Coen C C W Bongers, Mihai G Netea, Jos W van der Meer, Thijs M H Eijsvogels, Maria T E Hopman
PURPOSE: Exercise increases core body temperature (TC) due to metabolic heat production. However, the exercise-induced release of inflammatory cytokines including interleukin-6 may also contribute to the rise in TC by increasing the hypothalamic temperature setpoint. We aimed to investigate whether the exercise-induced increase in TC is partly caused by an altered hypothalamic temperature setpoint. METHODS: 15 healthy, active male subjects aged 36±14 years were recruited...
September 26, 2016: International Journal of Sports Physiology and Performance
Kuo Du, Anup Ramachandran, Hartmut Jaeschke
Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death...
October 4, 2016: Redox Biology
Yan Jiang, Feng-Jie Liu, Yu-Mei Wang, Hui-Jun Li
Although natural products (NPs) from ethnomedical plants have played a vital role in modern drug discovery, separation and purification of bioactive compounds from plant extract is still challenging. In this study, a dereplication strategy using HPLC-QTOF-MS was employed to rapidly discover and highly targeted isolate the novel hepatoprotective triterpenoid saponins from the methanol extract of Celosiae Semen. Firstly, four known saponins, i.e. celosin H, celosin I, celosin J, and pseudoginsenoside RT1 were selected as model compounds, and their fragmentation patterns in ESI-QTOF-MS/MS were characterized...
October 3, 2016: Journal of Pharmaceutical and Biomedical Analysis
Chun Pang, Liang Shi, Yuchen Sheng, Zhiyong Zheng, Hai Wei, Zhengtao Wang, Lili Ji
Caffeic acid (CA) is a natural compound abundant in fruits, coffee and plants. This study aims to investigate the involved mechanism of the therapeutic detoxification of CA against acetaminophen (APAP)-induced hepatotoxicity. CA (10, 30 mg/kg) was orally given to mice at 1 h after mice were pre-administrated with APAP (300 mg/kg). The therapeutic detoxification of CA against APAP-induced hepatotoxicity was observed by detecting serum aminotransferases, liver malondialdehyde (MDA) amount and liver histological evaluation in vivo...
October 6, 2016: Chemico-biological Interactions
Dushani L Palliyaguru, Dionysios V Chartoumpekis, Nobunao Wakabayashi, John J Skoko, Yoko Yagishita, Shivendra V Singh, Thomas W Kensler
Small molecules of plant origin offer presumptively safe opportunities to prevent carcinogenesis, mutagenesis and other forms of toxicity in humans. However, the mechanisms of action of such plant-based agents remain largely unknown. In recent years the stress responsive transcription factor Nrf2 has been validated as a target for disease chemoprevention. Withania somnifera (WS) is a herb used in Ayurveda (an ancient form of medicine in South Asia). In the recent past, withanolides isolated from WS, such as Withaferin A (WA) have been demonstrated to be preventive and therapeutic against multiple diseases in experimental models...
October 4, 2016: Free Radical Biology & Medicine
Zongmei Wen, Zhen Lei, Lu Yao, Ping Jiang, Tao Gu, Feng Ren, Yan Liu, Chunyan Gou, Xiuhui Li, Tao Wen
Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production...
2016: Cell Death & Disease
Yakov M Koen, Ke Liu, Heather Shinogle, Todd D Williams, Robert P Hanzlik
The hepatotoxicity of acetaminophen (APAP) is generally attributed to the formation of a reactive quinoneimine metabolite (NAPQI) that depletes glutathione and covalently binds to hepatocellular proteins. To explore the importance of the N-acyl group in APAP metabolism and toxicity, we synthesized 12 acyl side chain homologues of acetaminophen (APAP) and its 3'-regioisomer (AMAP), including the respective N-(4-pentynoyl) analogues PYPAP and PYMAP. Rat hepatocytes converted APAP, AMAP, PYPAP, and PYMAP extensively to O-glucuronide and O-sulfate conjugates in varying proportions, whereas glutathione or cysteine conjugates were observed only for APAP and PYPAP...
October 13, 2016: Chemical Research in Toxicology
Kai Yuan, Xue Zhang, Lei Lv, Jiwei Zhang, Wei Liang, Peng Wang
Treatment of acetaminophen (APAP) in overdose can cause a potentially serious and fatal liver injury. MicroRNA-155 (miR-155), a multifunctional microRNA, is known to mediate inflammatory responses via regulating various target genes. In this study, we aimed to study the role of miR-155 in APAP-induced liver injury, using miR-155-/- mice and miR-155 in vivo intervention. We noted that miR-155 expression was significantly increased in liver and blood after APAP treatment. Knockout of miR-155 deteriorated APAP-induced liver damage, with the elevated serum levels of AST and ALT...
September 24, 2016: International Immunopharmacology
Maranda Esterhuizen-Londt, Katrin Schwartz, Stephan Pflugmacher
The increasing anthropogenic pollution of aquatic environments and fresh water scarcity worldwide have prompted the development of low-cost and effective water treatment alternatives. One example of a highly released anthropogenic xenobiotics is acetaminophen (APAP), which has been detected in surface waters at concentrations as high as 5 μg L(-1). To date, traditional water treatment plants were unable to remove all pharmaceutical xenobiotics and as in the case with APAP, the breakdown products are toxic...
October 2016: Fungal Biology
Yuan Gao, Zhijun Cao, Xi Yang, Mohamed A Abdelmegeed, Jinchun Sun, Si Chen, Richard D Beger, Kelly Davis, William F Salminen, Byoung-Joon Song, Donna L Mendrick, Li-Rong Yu
Overdose of acetaminophen (APAP) is a major cause of acute liver failure. To identify pathways related to hepatotoxicity and potential biomarkers of liver injury, a proteomic approach of (16) O/(18) O labeling and 2D-LC-MS/MS was used to analyze liver tissues from rats at 6 and 24 h post-treatment with low (100 mg/kg) and high (1250 mg/kg) doses of APAP. The analysis revealed that molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner...
September 16, 2016: Proteomics. Clinical Applications
Hiromi Kusama, Kazuyoshi Kon, Kenichi Ikejima, Kumiko Arai, Tomonori Aoyama, Akira Uchiyama, Shunhei Yamashina, Sumio Watanabe
BACKGROUND: Acetaminophen (APAP) overdose induces severe oxidative stress followed by hepatocyte apoptosis/necrosis. Previous studies have indicated that endoplasmic reticulum (ER) stress is involved in the cell death process. Therefore, we investigated the effect of the chemical chaperone 4-phenyl butyric acid (PBA) on APAP-induced liver injury in mice. METHODS: Eight-week-old male C57Bl6/J mice were given a single intraperitoneal (i.p.) injection of APAP (450 mg/kg body weight), following which some were repeatedly injected with PBA (120 mg/kg body weight, i...
September 6, 2016: Journal of Gastroenterology
Kuo Xu, Zi-Ming Feng, Ya-Nan Yang, Jian-Shuang Jiang, Pei-Cheng Zhang
Phytochemical and pharmacological study on the rhizomes of Atractylodes lancea led to the identification of twenty-one compounds: six new eudesmane-type sesquiterpenoids (1-6), two new eremophilane-type sesquiterpenoids (7, 8), and thirteen known compounds (9-21). These new compounds were elucidated using extensive spectroscopic analyses with experimental and calculated electronic circular dichroism (ECD) for the configurational assignments. Notably, this study was the first report on the isolation of two eremophilane-type sesquiterpenoids (7, 8) from the genus Atractylodes...
October 2016: Fitoterapia
Mesfin Yimam, Ping Jiao, Mei Hong, Qi Jia
Historically, botanicals have been reported to possess good antioxidative activities as demonstrated by their free radical scavenging property rendering their usage in liver protection. In this study, we describe the potential use of MAP, a standardized blend comprising three extracts from Myristica fragrans, Astragalus membranaceus, and Poria cocos, in ameliorating chemically induced acute liver toxicities. Acetaminophen (APAP) and carbon tetrachloride (CCl4)-induced acute liver toxicity models in mice were utilized...
August 26, 2016: Journal of Medicinal Food
Kuo Du, Anup Ramachandran, James L Weemhoff, Hemantkumar Chavan, Yuchao Xie, Partha Krishnamurthy, Hartmut Jaeschke
Overdose of acetaminophen (APAP) causes severe liver injury and even acute liver failure in both mice and human. A recent study by Kim et al. (2015) showed that metformin, a first-line drug to treat type 2 diabetes mellitus, protected against APAP hepatotoxicity in mice. However, its exact protective mechanism has not been well clarified. To investigate this, C57BL/6J mice were treated with 400 mg/kg APAP and 350 mg/kg metformin was given 0.5h pre- or 2h post-APAP. Our data showed that pretreatment with metformin protected against APAP hepatotoxicity, as indicated by the over 80% reduction in plasma ALT activities and significant decrease in centrilobular necrosis...
August 25, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Jianqiao Zhang, Leiming Zhang, Xue Sun, Yanting Yang, Liang Kong, Chengwen Lu, Guangyao Lv, Tian Wang, Hongbo Wang, Fenghua Fu
Acetaminophen (APAP) is widely used as an analgesic and antipyretic agent, but it may induce acute liver injury at high doses. Alzheimer's disease patients, while treated with acetylcholinesterase inhibitor (AChEI), may take APAP when they suffer from cold or pain. It is generally recognized that inhibiting acetylcholinesterase activity may also result in liver injury. To clarify whether AChEI could deteriorate or attenuate APAP hepatotoxicity, the effects of AChEI on APAP hepatotoxicity were investigated. Male C57BL/6J mice were administrated with the muscarinic acetylcholine receptor (mAChR) blocker atropine (Atr), or classic α7 nicotine acetylcholine receptor (α7nAChR) antagonist methyllycaconitine (MLA) 1 hour before administration of AChEIs-donepezil (4 mg/kg), rivastigmine (2 mg/kg), huperzine A (0...
November 2016: Journal of Pharmacology and Experimental Therapeutics
Takeshi Mochizuki, Koichiro Yano, Katsunori Ikari, Ryo Hiroshima, Hiromitsu Takaoka, Kosei Kawakami, Naoko Koenuma, Mina Ishibashi, Toshikatsu Shirahata, Shigeki Momohara
BACKGROUND: While many of the commonly used treatments for perioperative pain after total knee arthroplasty (TKA) have been recognized as effective, there is still insufficient evidence for oral medication. In orthopedics, non-steroidal anti-inflammatory drugs (NSAIDs) have been commonly used for perioperative pain; however, serious adverse events have been reported. Conversely, tramadol hydrochloride/acetaminophen combination (TRAM/APAP) therapy has been shown to reduce pain, particularly for chronic pain in Japan...
September 2016: Journal of Orthopaedic Science: Official Journal of the Japanese Orthopaedic Association
Minjeong Kim, Jun-Won Yun, Kyeho Shin, Yejin Cho, Mijeong Yang, Ki Taek Nam, Kyung-Min Lim
Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity...
August 19, 2016: Biomolecules & Therapeutics
Jacqueline Calvano, Gwendolyn Edwards, Clifford Hixson, Holly Burr, Raja Mangipudy, Mark Tirmenstein
Pancreatic injury in rats is primarily detected through histopathological changes and conventional serum biomarkers such as amylase and lipase. However, amylase and lipase have a short half-life and are markers of acinar, not islet cell injury. We investigated whether circulating microRNA (miR) levels that are enriched in acinar cells (miR-217, miR-216a/b) or islet cells (miR-375) could serve as markers of pancreatic injury. Rats were treated with a single dose of either vehicle, streptozotocin (STZ), caerulein, or acetaminophen (APAP), and necropsied at 4, 24, and 48h...
August 10, 2016: Toxicology
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