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https://www.readbyqxmd.com/read/28717109/utility-of-human-hepatocyte-spheroids-without-feeder-cells-for-evaluation-of-hepatotoxicity
#1
Takuo Ogihara, Hiroshi Arakawa, Tomoko Jomura, Yoko Idota, Satoshi Koyama, Kentaro Yano, Hajime Kojima
We investigated the utility of three-dimensionally cultured hepatocytes (spheroids) without feeder cells (Sph(f-)) for the prediction of drug-induced liver injury (DILI) in humans. Sph(f-) and spheroids cultured on feeder cells (Sph(f+)) were exposed to the hepatotoxic drugs flutamide, diclofenac, isoniazid and chlorpromazine at various concentrations for 14 days, and albumin secretion and cumulative leakages of toxicity marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GTP), were measured...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28717101/mechanism-based-risk-assessment-strategy-for-drug-induced-cholestasis-using-the-transcriptional-benchmark-dose-derived-by-toxicogenomics
#2
Taisuke Kawamoto, Yuichi Ito, Osamu Morita, Hiroshi Honda
Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28713494/caspase-3-role-and-immunohistochemical-expression-in-assessment-of-apoptosis-as-a-feature-of-h1n1-vaccine-caused-drug-induced-liver-injury-dili
#3
Abir Khalil Mohamed, Mona Magdy
BACKGROUND: Drug-Induced Liver Injury (DILI) changes, occur post exposure to natural or chemical compounds including apoptosis. AIM: To assess the H1N1 vaccine-caused DILI by histochemical and immunohistochemical methods. METHODS: This 2014's experimental study was conducted on 70 albino rats. They were given Arepanrix(TM) H1N1 vaccine and were divided into 7 groups; 10 mice each, as control (non-vaccinated), vac2 and vac4 injected with 1(st) and 2(nd) doses of vaccine (suspension only) and euthanized after 3 weeks each, vac5 euthanized 6 weeks after 2(nd) dose, mix2 and mix4 injected with 1(st) and 2(nd) doses of vaccine (mixture of suspension and adjuvant) and euthanized after 3 weeks each, mix5 and euthanized 6 weeks after 2(nd) dose...
May 2017: Electronic Physician
https://www.readbyqxmd.com/read/28702139/ramipril-associated-cholestasis-in-the-setting-of-recurrent-drug-induced-liver-injury
#4
David Forner, Tasha Kulai, Thomas Arnason, Steven E Gruchy, Magnus MacLeod
Aim: Angiotensin-converting enzyme inhibitors (ACEIs) are commonly used to treat hypertension. Although generally well tolerated, the adverse effects of ACEIs include hypotension, cough, acute kidney injury and hyperkalemia. Rare reports of ACEI-induced hepatotoxicity have been described, most notably a cholestatic pattern of injury related to captopril. A 67-year-old male presented to the emergency department with a three-week history of jaundice, pruritis and weakness. Eight weeks before, he began taking ramipril and clopidogrel...
2017: Gastroenterology and Hepatology From Bed to Bench
https://www.readbyqxmd.com/read/28694671/substantial-hepatic-necrosis-is-prognostic-in-fulminant-liver-failure
#5
Paul Ndekwe, Marwan S Ghabril, Yong Zang, Steven A Mann, Oscar W Cummings, Jingmei Lin
AIM: To evaluate if any association existed between the extent of hepatic necrosis in initial liver biopsies and patient survival. METHODS: Thirty-seven patients with fulminant liver failure, whose liver biopsy exhibited substantial necrosis, were identified and included in the study. The histological and clinical data was then analyzed in order to assess the relationship between the extent of necrosis and patient survival, with and without liver transplantation...
June 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28691103/role-of-nonalcoholic-fatty-liver-disease-as-risk-factor-for-drug-induced-hepatotoxicity
#6
Julie Massart, Karima Begriche, Caroline Moreau, Bernard Fromenty
BACKGROUND: Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. AIM: The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity...
February 2017: Journal of Clinical and Translational Research
https://www.readbyqxmd.com/read/28688954/rifampicin-induced-injury-in-hepg2-cells-is-alleviated-by-tudca-via-increasing-bile-acid-transporters-expression-and-enhancing-the-nrf2-mediated-adaptive-response
#7
Weiping Zhang, Lihong Chen, Hui Feng, Wei Wang, Yi Cai, Fen Qi, Xiaofang Tao, Jun Liu, Yujun Shen, Xiaofei Ren, Xi Chen, Jianming Xu, Yuxian Shen
Bile acid transporters and the nuclear factor erythroid 2-related factor (Nrf-2)-mediated adaptive response play important roles in the development of drug-induced liver injury (DILI). However, little is known about the contribution of the adaptive response to rifampicin (RFP)-induced cell injury. In this study, we found RFP decreased the survival rate of HepG2 cells and increased the levels of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), γ-glutamyl-transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total bile acid (TBA) and adenosine triphosphate (ATP) in the cell culture supernatants in both a concentration- and a time-dependent manner...
July 5, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28675685/challenges-and-difficulties-in-pathological-diagnosis-of-autoimmune-hepatitis
#8
REVIEW
Kenichi Harada, Nguyen Canh Hiep, Hiromasa Ohira
Autoimmune hepatitis (AIH) with acute presentation is widely recognized as a distinct clinical entity, and its clinicopathology has been extensively studied. In most cases, AIH with acute presentation is merely acute exacerbation of classical chronic AIH, but pure acute-onset AIH without previous symptoms of chronic liver disease is also encountered. Rapid diagnosis and initiation of immunosuppressive treatment are necessary for both acute exacerbation and acute-onset to prevent fatal liver failure. The diagnostic criteria commonly used for classical AIH are generally applicable to acute exacerbation, but acute-onset AIH may present with additional pathological features...
July 3, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/28675031/efficient-two-photon-fluorescent-probe-for-glutathione-s-transferase-detection-and-imaging-in-drug-induced-liver-injury-sample
#9
Jing Zhang, Zhen Jin, Xiao-Xiao Hu, Hong-Min Meng, Jin Li, Xiao-Bing Zhang, Hong-Wen Liu, Tanggang Deng, Shan Yao, Lili Feng
Drug-induced liver injury (DILI) is a potential complication of any prescribed medication. So far, the diagnosis of DILI is still a clinical challenge due to the lack of efficient diagnosis method. Glutathione S-transferase (GST), with a high concentration in liver cytosol, can reduce toxicity and facilitate urinary excretion by catalyzing the conjugation of glutathione (GSH) with reactive metabolites in liver. When liver is seriously damaged, GST and GSH will be released into plasma from liver cytosol, which caused a lower GST activity in liver cytosol...
July 4, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28674261/preliminary-evaluation-of-three-dimensional-primary-human-hepatocyte-culture-system-for-assay-of-drug-metabolizing-enzyme-inducing-potential
#10
Hiroshi Arakawa, Hiroki Kamioka, Tomoko Jomura, Satoshi Koyama, Yoko Idota, Kentaro Yano, Hajime Kojima, Takuo Ogihara
Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR))...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28671602/mechanism-investigation-of-rifampicin-induced-liver-injury-using-comparative-toxicoproteomics-in-mice
#11
Ju-Hyun Kim, Woong Shik Nam, Sun Joo Kim, Oh Kwang Kwon, Eun Ji Seung, Jung Jae Jo, Riya Shresha, Tae Hee Lee, Tae Won Jeon, Sung Hwan Ki, Hye Suk Lee, Sangkyu Lee
Tuberculosis is one of the top causes of death among curable infectious diseases; it is an airborne infectious disease that killed 1.1 million people worldwide in 2010. Anti-tuberculosis drug-induced liver injury is the primary cause of drug-induced liver injury (DILI). Rifampicin is one of the most common anti-tuberculosis therapies and has well-known hepatotoxicity. To understand the mechanism of rifampicin-induced liver injury, we performed a global proteomic analysis of liver proteins by LC-MS/MS in a mouse model after the oral administration of 177 and 442...
July 2, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28671182/a-transcriptomics-data-driven-gene-space-accurately-predicts-liver-cytopathology-and-drug-induced-liver-injury
#12
Pekka Kohonen, Juuso A Parkkinen, Egon L Willighagen, Rebecca Ceder, Krister Wennerberg, Samuel Kaski, Roland C Grafström
Predicting unanticipated harmful effects of chemicals and drug molecules is a difficult and costly task. Here we utilize a 'big data compacting and data fusion'-concept to capture diverse adverse outcomes on cellular and organismal levels. The approach generates from transcriptomics data set a 'predictive toxicogenomics space' (PTGS) tool composed of 1,331 genes distributed over 14 overlapping cytotoxicity-related gene space components. Involving ∼2.5 × 10(8) data points and 1,300 compounds to construct and validate the PTGS, the tool serves to: explain dose-dependent cytotoxicity effects, provide a virtual cytotoxicity probability estimate intrinsic to omics data, predict chemically-induced pathological states in liver resulting from repeated dosing of rats, and furthermore, predict human drug-induced liver injury (DILI) from hepatocyte experiments...
July 3, 2017: Nature Communications
https://www.readbyqxmd.com/read/28663501/plant-diversity-increases-with-the-strength-of-negative-density-dependence-at-the-global-scale
#13
Joseph A LaManna, Scott A Mangan, Alfonso Alonso, Norman A Bourg, Warren Y Brockelman, Sarayudh Bunyavejchewin, Li-Wan Chang, Jyh-Min Chiang, George B Chuyong, Keith Clay, Richard Condit, Susan Cordell, Stuart J Davies, Tucker J Furniss, Christian P Giardina, I A U Nimal Gunatilleke, C V Savitri Gunatilleke, Fangliang He, Robert W Howe, Stephen P Hubbell, Chang-Fu Hsieh, Faith M Inman-Narahari, David Janík, Daniel J Johnson, David Kenfack, Lisa Korte, Kamil Král, Andrew J Larson, James A Lutz, Sean M McMahon, William J McShea, Hervé R Memiaghe, Anuttara Nathalang, Vojtech Novotny, Perry S Ong, David A Orwig, Rebecca Ostertag, Geoffrey G Parker, Richard P Phillips, Lawren Sack, I-Fang Sun, J Sebastián Tello, Duncan W Thomas, Benjamin L Turner, Dilys M Vela Díaz, Tomáš Vrška, George D Weiblen, Amy Wolf, Sandra Yap, Jonathan A Myers
Theory predicts that higher biodiversity in the tropics is maintained by specialized interactions among plants and their natural enemies that result in conspecific negative density dependence (CNDD). By using more than 3000 species and nearly 2.4 million trees across 24 forest plots worldwide, we show that global patterns in tree species diversity reflect not only stronger CNDD at tropical versus temperate latitudes but also a latitudinal shift in the relationship between CNDD and species abundance. CNDD was stronger for rare species at tropical versus temperate latitudes, potentially causing the persistence of greater numbers of rare species in the tropics...
June 30, 2017: Science
https://www.readbyqxmd.com/read/28652195/predicting-drug-induced-liver-injury-the-importance-of-data-curation
#14
Eleni Kotsampasakou, Floriane Montanari, Gerhard F Ecker
Drug-induced liver injury (DILI) is a major issue for both patients and pharmaceutical industry due to insufficient means of prevention/prediction. In the current work we present a 2-class classification model for DILI, generated with Random Forest and 2D molecular descriptors on a dataset of 966 compounds. In addition, predicted transporter inhibition profiles were also included into the models. The initially compiled dataset of 1773 compounds was reduced via a 2-step approach to 966 compounds, resulting in a significant increase (p-value<0...
June 23, 2017: Toxicology
https://www.readbyqxmd.com/read/28645575/prediction-of-drug-induced-immune-mediated-hepatotoxicity-using-hepatocyte-like-cells-derived-from-human-embryonic-stem-cells
#15
Dong Eon Kim, Mi-Jin Jang, Young Ran Kim, Joo-Young Lee, Eun Byul Cho, Eunha Kim, Yeji Kim, Mi Young Kim, Won-Il Jeong, Seyun Kim, Yong-Mahn Han, Seung-Hyo Lee
Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events...
June 20, 2017: Toxicology
https://www.readbyqxmd.com/read/28640208/associations-of-drug-lipophilicity-and-extent-of-metabolism-with-drug-induced-liver-injury
#16
Kristin McEuen, Jürgen Borlak, Weida Tong, Minjun Chen
Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI...
June 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28627888/investigation-of-drug-induced-hepatotoxicity-and-its-remediation-pathway-with-reaction-based-fluorescent-probes
#17
Dan Cheng, Wang Xu, Lin Yuan, Xiaobing Zhang
Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO(-)) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO(-) and Rhod-ONOO(-)) for ONOO(-) through a novel and universally applicable mechanism: ONOO(-)-mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO(-) can selectively accumulate and react in mitochondria, one of the main sources of ONOO(-), with a substantial lower nanomolar sensitivity of 43 nM...
July 6, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28617228/prediction-models-for-drug-induced-hepatotoxicity-by-using-weighted-molecular-fingerprints
#18
Eunyoung Kim, Hojung Nam
BACKGROUND: Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints. RESULTS: In this study, we used 881 bits of molecular fingerprint and used as features describing presence or absence of each substructure of compounds...
May 31, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28616908/-the-correlation-between-micrornas-in-serum-and-the-extent-of-liver-injury
#19
Yi-Nan Zuo, Xue-Ling He, Xue-Ni Shi, Shi-Hang Wei, Hai-Lin Yin
OBJECTIVES: To investigate the correlation between the absolute quantification of the microRNAs (miR-122, miR-451, miR-92a, miR-192) in serum during acute liver injury and the extent of liver injury on rat models of CCl4 induced acute liver injury and mice models of acetaminophen (APAP) induced acute liver injury. Furthermore, to investigate the correlation between the absolute quantification of microRNAs in serum and the drug induced liver injury pathological scoring system (DILI-PSS)...
May 2017: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
https://www.readbyqxmd.com/read/28615926/mechanistic-modelling-of-drug-induced-liver-injury-investigating-the-role-of-innate-immune-responses
#20
Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell
Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration...
2017: Gene Regulation and Systems Biology
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