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acetaminophen and liver

Jacquelyn O Russell, Sungjin Ko, Harvinder S Saggi, Sucha Singh, Minakshi Poddar, Donghun Shin, Satdarshan P Monga
Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins like JQ1 have shown efficacy in preclinical cancer models including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration...
March 12, 2018: American Journal of Pathology
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
Yan Zhang, Zhongyuan Huang, Letao Wang, Chunming Wang, Changde Zhang, Thomas E Wiese, Guangdi Wang, Kevin Eugene Riley, Zhe Wang
This work aims to face the challenge of monitoring small molecule drugs accurately and rapidly for point-of-care (POC) diagnosis in current clinical settings. Overdose of acetaminophen (AP), a commonly used OTC analgesic drug, has been determined to be a major cause of acute liver failure in the US and the UK. However, there is no rapid and accurate detection method available for this drug in the emergency room. The present study examined an AP sensing strategy that relies on a previously unexplored strong interaction between AP and the arginine (Arg) molecule...
March 15, 2018: Analytical Chemistry
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
Andrew J Lutkewitte, George G Schweitzer, Stefanie Kennon-McGill, Melissa M Clemens, Laura P James, Hartmut Jaeschke, Brian N Finck, Mitchell R McGill
No abstract text is available yet for this article.
March 10, 2018: Food and Chemical Toxicology
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
Michael Riverso, Michael Chang, Consuelo Soldevila-Pico, Jinping Lai, Xiuli Liu
Kratom is an herbal product derived from the leaves of Southeast Asian Mitragyna speciosa trees. It has traditionally been used by indigenous people to relieve fatigue and manage pain, diarrhea, or opioid withdrawal. The use of kratom has become more commonplace in the United States for similar purposes. Only rare reports of kratom liver toxicity exist in the literature but without histologic characterization. Herein, we report one case of kratom use-associated liver toxicity in a 38-year-old patient. The patient complained of dark colored urine and light colored stools after using kratom...
February 2018: Gastroenterology Research
Preeti Viswanathan, Yogeshwar Sharma, Priya Gupta, Sanjeev Gupta
OBJECTIVES: Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. MATERIALS AND METHODS: Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure...
March 5, 2018: Cell Proliferation
Eugene Choi, Derek Alsop, Joanna Y Wilson
In this study, we examined if rainbow trout chronically exposed to acetaminophen (10 and 30 μgL-1 ) showed histological changes that coincided with functional changes in the kidney, gill and liver. Histological changes in the kidney included movement and loss of nuclei, non-uniform nuclei size, non-uniform cytoplasmic staining, and loss of tubule integrity. Histological effects were more severe at the higher concentration and coincided with concentration dependent increases in urine flow rate and increased urinary concentrations of sodium, chloride, potassium, calcium, urea, ammonia, glucose, and protein...
February 15, 2018: Aquatic Toxicology
Jessica R Salas, Bao Ying Chen, Alicia Wong, Sergio Duarte, Stephanie A K Angarita, Gerald S Lipshutz, Owen N Witte, Peter M Clark
Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed. Methods: We evaluate in a preclinical model whether18 F-2-deoxy-2-fluoroarabinose (18 F-DFA), a PET radiotracer that measures the ribose salvage pathway, can be used to monitor acetaminophen-induced liver injury and failure...
March 1, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Takuma Iguchi, Ken Sakurai, Satoshi Tamai, Kazuhiko Mori
Circulating microRNAs (miRNAs) can potentially be used as sensitive and specific biomarkers for tissue injury. However, the usefulness of circulating miRNAs as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific miRNAs. Therefore, a systematic investigation was performed to address this point. We identified organ-specific miRNAs from cynomolgus monkeys by next-generation sequencing analysis, which revealed that miR-122 was only abundant in the liver, whereas miR-192 was abundant in the liver, stomach, intestines, and kidney...
January 2018: Journal of Toxicologic Pathology
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
Angela L Chiew, Christian Gluud, Jesper Brok, Nick A Buckley
BACKGROUND: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites...
February 23, 2018: Cochrane Database of Systematic Reviews
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
Abigail Zabron, Alberto Quaglia, Evangelia Fatourou, Praveen Peddu, Dylan Lewis, Michael Heneghan, Christopher Willars, Georg Auzinger, Nigel Heaton, Julia Wendon, Pauline Kane, John Karani, William Bernal
BACKGROUND: Liver volume (LV) can be non-invasively determined from analysis of computed tomography (CT) images, and in patients with Acute liver injury (ALI) or failure (ALF) reflect the balance of structural collapse with hepatic regeneration. We examined its relation to cause of liver injury, measures of liver function and histopathological findings, and utility in prediction of complications and mortality. METHODS: 273 patients with ALF/ALI admitted to a specialist intensive care unit were studied...
February 20, 2018: Liver International: Official Journal of the International Association for the Study of the Liver
Shengli Mi, Xiaoman Yi, Zhichang Du, Yuanyuan Xu, Wei Sun
The liver is one of the main metabolic organs, and nearly all ingested drugs will be metabolized by the liver. Only a small fraction of drugs are able to come onto the market during drug development, and hepatic toxicity is a major cause for drug failure. Since drug development is costly in both time and materials, an in vitro liver model that can accelerate bioreactions in the liver and reduce drug consumption is imperative in the pharmaceutical industry. The liver on a chip is an ideal alternative for its controllable environment and tiny size, which means constructing a more biomimetic model, reducing material consumption as well as promoting drug diffusion and reaction...
February 20, 2018: Biofabrication
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
Mohsen Sarikhani, Sneha Mishra, Perumal Arumugam Desingu, Chaithanya Kotyada, Donald Wolfgeher, Mahesh P Gupta, Mahavir Singh, Nagalingam R Sundaresan
c-Jun NH 2 -terminal kinases (JNKs) are responsive to stress stimuli and their activation regulate key cellular functions, including cell survival, growth, differentiation and aging. Previous studies demonstrate that activation of JNK requires dual phosphorylation by the mitogen-activated protein kinase kinases. However, other post-translational mechanisms involved in regulating the activity of JNK have been poorly understood. In this work, we studied the functional significance of reversible lysine acetylation in regulating the kinase activity of JNK...
February 15, 2018: Cell Death and Differentiation
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