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https://www.readbyqxmd.com/read/29355688/metabolomics-profiling-of-steatosis-progression-in-heparg%C3%A2-cells-using-sodium-valproate
#1
Matthias Cuykx, Leen Claes, Robim M Rodrigues, Tamara Vanhaecke, Adrian Covaci
Non-alcoholic Fatty Liver Disease (NAFLD) is a frequently encountered Drug-Induced Liver Injury (DILI). Although this stage of the disease is reversible, it can lead to irreversible damage provoked by non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Therefore, the assessment of NAFLD is a paramount objective in toxicological screenings of new drug candidates. In this study, a metabolomic fingerprint of NAFLD induced in HepaRG® cells at four dosing schemes by a reference toxicant, sodium valproate (NaVPA), was obtained using liquid-liquid extraction followed by liquid chromatography and accurate mass-mass spectrometry (LC-AM/MS)...
January 17, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29355632/in-vivo-anti-psoriatic-activity-biodistribution-sub-acute-and-sub-chronic-toxicity-studies-of-orally-administered-methotrexate-loaded-chitin-nanogel-in-comparison-with-methotrexate-tablet
#2
Rajitha Panonnummal, R Jayakumar, Gopikrishnan Anjaneyan, M Sabitha
The anti-psoriatic efficacy of orally administered methotrexate loaded chitin nanogel (MCNG) was evaluated (two doses- 2.715 mg/kg and 5.143 mg/kg) and compared against orally administered methotrexate tablet MTX (5.143 mg/kg). MCNG at both dose levels of 2.715 mg/kg and 5.143 mg/kg exhibited significant anti-psoriatic activity which is very much comparable with MTX, caused normalization of histological features and inflammatory score associated with induced psoriasis. Biodistribution studies revealed the presence of drug in serum and in vital organs at all the three cases with highest amount in MCNG at 5...
January 17, 2018: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29355553/new-application-of-the-commercial-sweetener-rebaudioside-a-as-a-hepatoprotective-candidate-induction-of-the-nrf2-signaling-pathway
#3
Yuxin Wang, Linyao Li, Yawen Wang, Xiaokang Zhu, Mingdong Jiang, Erqun Song, Yang Song
A large population of drug candidates have failed "from bench to bed" due to unwanted toxicities. We intend to develop an alternative approach for drug discovery, that is, to seek candidates from "safe" compounds. Rebaudioside A (Reb-A) is an approved commercial sweetener from Stevia rebaudiana Bertoni. We found that Reb-A protects against carbon tetrachloride (CCl4)-induced oxidative injury in human liver hepatocellular carcinoma (HepG2) cells. Reb-A showed antioxidant activity on reducing cellular reactive oxygen species and malondialdehyde levels while increasing glutathione levels and superoxide dismutase and catalase activities...
January 17, 2018: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29355304/computationally-assessing-the-bioactivation-of-drugs-by-n-dealkylation
#4
Na Le Dang, Tyler B Hughes, Grover Paul Miller, S Joshua Swamidass
Cytochromes P450 (CYPs) oxidize alkylated amines commonly found in drugs and other biologically active molecules, splitting them into an amine and an aldehyde. Metabolic studies usually neglect to report or investigate aldehydes, even though they can be toxic. It is assumed that they are efficiently detoxified into carboxylic acids and alcohols. Nevertheless, some aldehydes are reactive and escape detoxification pathways to cause adverse events by forming DNA and protein adducts. Herein, we modeled N-dealkylations that produce both amine and aldehyde metabolites and then predicted the reactivity of the aldehyde...
January 22, 2018: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/29353652/modeling-of-normal-tissue-complications-using-imaging-and-biomarkers-after-radiation-therapy-for-hepatocellular-carcinoma
#5
Issam El Naqa, Adam Johansson, Dawn Owen, Kyle Cuneo, Yue Cao, Martha Matuszak, Latifa Bazzi, Theodore S Lawrence, Randall K Ten Haken
PURPOSE: To develop normal tissue complications (NTCP) models for hepatocellular cancer (HCC) patients who undergo liver radiation therapy (RT) and to evaluate the potential role of functional imaging and measurement of blood-based circulating biological markers before and during RT to improve the performance of these models. METHODS AND MATERIALS: The data from 192 HCC patients who had undergone RT from 2005 to 2014 were evaluated. Of the 192 patients, 146 had received stereotactic body RT (SBRT) and 46 had received conventional RT to a median physical tumor dose of 49...
February 1, 2018: International Journal of Radiation Oncology, Biology, Physics
https://www.readbyqxmd.com/read/29353386/population-based-dose-response-analysis-of-liver-transcriptional-response-to-trichloroethylene-in-mouse
#6
Abhishek Venkatratnam, John S House, Kranti Konganti, Connor McKenney, David W Threadgill, Weihsueh A Chiu, David L Aylor, Fred A Wright, Ivan Rusyn
Studies of gene expression are common in toxicology and provide important clues to mechanistic understanding of adverse effects of chemicals. Most prior studies have been performed in a single strain or cell line; however, gene expression is heavily influenced by the genetic background, and these genotype-expression differences may be key drivers of inter-individual variation in response to chemical toxicity. In this study, we hypothesized that the genetically diverse Collaborative Cross mouse population can be used to gain insight and suggest mechanistic hypotheses for the dose- and genetic background-dependent effects of chemical exposure...
January 20, 2018: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/29353166/toxicological-responses-on-cytochrome-p450-and-metabolic-transferases-in-liver-of-goldfish-carassius-auratus-exposed-to-lead-and-paraquat
#7
Xiaoming Xu, Zhaojie Cui, Xinlei Wang, Xixin Wang, Su Zhang
As the producer of reactive oxygen species (ROS), both lead (Pb) and paraquat (PQ) can generate serious oxidative stress in target organs which result in irreversible toxic effects on organisms. They can disturb the normal catalytic activities of many enzymes by means of different toxicity mechanism. The changed responses of enzymes are frequently used as the biomarkers for indicating the relationship between toxicological effects and exposure levels. In this work, goldfish was exposed to a series of test groups containing lead and paraquat in the range of 0...
January 17, 2018: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/29353125/relationship-between-serum-trimethylamine-n-oxide-and-exposure-to-dioxin-like-pollutants
#8
Michael C Petriello, Richard Charnigo, Manjula Sunkara, Sony Soman, Marian Pavuk, Linda Birnbaum, Andrew J Morris, Bernhard Hennig
Trimethylamine N-oxide (TMAO) is a diet and gut microbiota-derived metabolite that has been linked to cardiovascular disease risk in human studies and animal models. TMAO levels show wide inter and intra individual variability in humans that can likely be accounted for by multiple factors including diet, the gut microbiota, levels of the TMAO generating liver enzyme Flavin-containing monooxygenase 3 (FMO3) and kidney function. We recently found that dioxin-like (DL) environmental pollutants increased FMO3 expression to elevate circulating diet-derived TMAO in mice, suggesting that exposure to this class of pollutants might also contribute to inter-individual variability in circulating TMAO levels in humans...
January 16, 2018: Environmental Research
https://www.readbyqxmd.com/read/29353062/microrna-in-rat-liver-sinusoidal-endothelial-cells-and-hepatocytes-and-application-to-circulating-biomarkers-that-discern-pathogenesis-of-liver-injuries
#9
Shingo Oda, Masaki Takeuchi, Sho Akai, Yuji Shirai, Koichi Tsuneyama, Tsuyoshi Yokoi
Sinusoidal obstruction syndrome is a serious liver injury caused by toxic injury to liver sinusoidal endothelial cells (LSECs) during clinical chemotherapy. Although circulating microRNAs (miRNAs), such as hepatocyte-specific miR-122-5p and miR-192-5p, have been proposed as potential noninvasive biomarkers of hepatocellular liver injury, these miRNAs may not be specific to damage to other hepatic cell types, including LSECs. Here, we characterized miRNA expression in LSECs and hepatocytes and investigated whether cell type-specific miRNAs in plasma can discern pathogenesis of liver injuries in rats...
January 15, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29352068/maternal-fetal-disposition-and-metabolism-of-retrorsine-in-pregnant-rats
#10
Xia Li, Xiaojing Yang, E Xiang, Jinyuan Luo, Shuaikai Qiu, Yan Fang, Li Zhang, Yu Guo, Jiang Zheng, Hui Wang
Pyrrolizidine alkaloids (PAs) are extensively synthesized by plants and are commonly present in herbs and foodstuffs, which exhibit hepatotoxicity requiring metabolic activation by cytochrome P450 (CYP) 3A to form the electrophilic metabolites-pyrrolic ester. PAs also cause embryo toxicity, but the metabolic profiles of PAs in fetus and placenta have been far from clear. In this study, we determined the basal metabolic activation of retrorsine (RTS) in rat maternal liver, placenta and fetal liver in vitro, and examined the fetal toxicity and bioactivation of RTS in vivo...
January 19, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29351480/mechanistically-different-effects-of-fat-and-sugar-on-insulin-resistance-hypertension-and-gut-microbiota-in-rats
#11
Sara Ramos-Romero, Mercè Hereu, Lidia Atienza, Josefina Casas, Olga Jáuregui, Susana Amézqueta, Gabriel Dasilva, Isabel Medina, Maria Rosa Nogués, Marta Romeu, Josep Lluís Torres
Insulin resistance (IR) and impaired glucose tolerance (IGT) are the first manifestations of diet-induced metabolic alterations leading to type-2 diabetes, while hypertension is the deadliest risk factor of cardiovascular disease. The roles of dietary fat and fructose in the development of IR, IGT and hypertension are controversial. We tested the long-term effects of an excess of fat or sucrose (fructose/glucose) on healthy male Wistar Kyoto (WKY) rats. Fat affects IR and IGT earlier than fructose through low-grade systemic inflammation evidenced by liver inflammatory infiltration, increased levels of plasma interleukin-6, prostaglandin E2 and reduced levels of protective short-chain fatty acids without triggering hypertension...
January 2, 2018: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29351251/compatibility-with-panax-notoginseng-and-rehmannia-glutinosa-alleviates-the-hepatotoxicity-and-nephrotoxicity-of-tripterygium-wilfordii-via-modulating-the-pharmacokinetics-of-triptolide
#12
Qichun Zhang, Yiqun Li, Mengzhu Liu, Jinao Duan, Xueping Zhou, Huaxu Zhu
Tripterygium wilfordii (TW) and the representative active component triptolide show positive therapeutic effect on the autoimmune disorders and simultaneously ineluctable hepatotoxicity and nephrotoxicity. Combinational application of Panax notoginseng (PN) and Rehmannia glutinosa (RG) weakens the toxicity of TW according the clinical application of traditional Chinese medicine. This article was aimed at the mechanism of decreasing toxicity of TW by the combinational application of PN and RG. Biochemical and pathohistological analysis were utilized to assess the toxicity on liver and kidney in rats administrated with TW, TW-PN, TW-RG and TW-PN-RG for 3 and 7 days...
January 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29349833/a-systematic-assessment-of-key-design-and-performance-characteristics-of-drug-exposure-registries-requested-by-the-u-s-food-and-drug-administration
#13
Yanling Zhao, Ellen Pinnow, Jacqueline M Major
PURPOSE: The purpose of the study is to evaluate contributions to postmarket safety assessments and identify potential factors for enhancing implementation and utilization of registries in regulatory decision-making. METHODS: Registry documents (e.g., protocols, reports) submitted to the FDA were identified up to January 2016 through an extensive, systematic review of internal records and resources. We characterized nonpregnancy drug exposure registries based on prespecified design elements, performance, and regulatory impact...
January 19, 2018: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/29349797/efficacy-and-toxicity-of-praziquantel-in-helminth-infected-barbel-barbus-barbus-l
#14
E Zuskova, V Piackova, J Machova, L Chupani, C Steinbach, A Stara, J Velisek
This study evaluated efficacy and toxicity of the pyrazinoisoquinoline anthelmintic praziquantel (PZQ) in barbel infected with metacercariae of Diplostomum spathaceum and adult Pomphorhynchus laevis, and assessed antioxidant biomarkers and the lipid peroxidation response in juvenile barbel post-treatment. The estimated 96-hr LC50 of PZQ was 28.6 mg/L. For evaluation of efficacy, barbel naturally infected with D. spathaceum were exposed to a 10 and 20 mg/L PZQ 4-day bath treatment. Both concentrations were 100% effective against D...
January 19, 2018: Journal of Fish Diseases
https://www.readbyqxmd.com/read/29348818/high-cyp2e1-activity-correlates-with-hepatofibrogenesis-induced-by-nitrosamines
#15
Jie Gao, Gao-Ju Wang, Zhao Wang, Na Gao, Jing Li, Yun-Fei Zhang, Jun Zhou, Hong-Xin Zhang, Qiang Wen, Han Jin, Hai-Ling Qiao
Hepatofibrosis, which leads to cirrhosis and eventual hepatocellular carcinoma, is a common response to chronic toxin-mediated liver injury. Nitrosamines are potent hepatotoxic agents that cause necrosis and subsequent fibrosis in the liver as a result of cytochrome P450 2E1 (CYP2E1)-dependent metabolism, which generates toxic metabolites that form adducts with nucleic acids, leading to hepatotoxicity and mutagenesis. Herein, CYP2E1 activity and content were determined in fibrotic liver tissue from patients with hepatocellular carcinoma...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29348380/effect-of-nigella-sativa-seed-extract-for-hypertension-in-elderly-a-double-blind-randomized-controlled-trial
#16
Aulia Rizka, Siti Setiati, Aida Lydia, Esthika Dewiasty
BACKGROUND: Nigella sativa (NS) seed extract shows diuretic activity, inhibits sympathetic nervous system overactivity and increases the production of Nitric Oxide in in vivo studies, thus it has a potential use as an adjuvant antihypertensive for elderly population. This study aimed to determine the effect of Nigella sativa seed extract to systolic blood pressure (SBP) and diastolic blood pressure (DBP) of elderly patients with hypertension. METHODS: a double-blind, randomized controlled trial was conducted on elderly subjects with hypertension in three outpatient clinics in Cipto Mangunkusumo National Hospital Jakarta Indonesia from June to September 2011...
October 2017: Acta Medica Indonesiana
https://www.readbyqxmd.com/read/29346131/toxicological-profile-and-safety-pharmacology-of-a-single-dose-of-fibroblast-activation-protein-%C3%AE-based-doxorubicin-prodrug-in-vitro-and-in-vivo-evaluation
#17
Sichao Huang, Yuchen Zhang, Jinsong Zhong, Ying Pan, Shaohui Cai, Jun Xu
Fibroblast activation protein-α (FAPα) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAPα has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAPα-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAPα...
January 17, 2018: Anti-cancer Drugs
https://www.readbyqxmd.com/read/29345251/cancer-associated-cachexia
#18
REVIEW
Vickie E Baracos, Lisa Martin, Murray Korc, Denis C Guttridge, Kenneth C H Fearon
Cancer-associated cachexia is a disorder characterized by loss of body weight with specific losses of skeletal muscle and adipose tissue. Cachexia is driven by a variable combination of reduced food intake and metabolic changes, including elevated energy expenditure, excess catabolism and inflammation. Cachexia is highly associated with cancers of the pancreas, oesophagus, stomach, lung, liver and bowel; this group of malignancies is responsible for half of all cancer deaths worldwide. Cachexia involves diverse mediators derived from the cancer cells and cells within the tumour microenvironment, including inflammatory and immune cells...
January 18, 2018: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/29344254/inhibitory-effect-of-the-low-toxic-exogenous-aryl-hydrocarbon-receptor-modulator-3-3-diindolylmethane-on-gastric-cancer-in-mice
#19
Mingli Su, Chenchen Qian, Yumin Hu, Wenhua Lu, Rongkang Huang, Minhu Chen, Jie Chen
3'3-Diindolylmethane (DIM) has been proved to exhibit anticancer properties in many solid tumors. In our previous study, we demonstrated that DIM inhibited SGC7901 cell proliferation by inducing apoptosis and delaying cell cycle progression. Herein, we further explored the anti-tumor effect of DIM on SGC-7901 tumor bearing mice. Tumors were excised, weighed, and tested by western blot and TdT-UTP nick-end labeling (TUNEL) assay. Blood samples were collected for biochemical analysis. The expression levels of AhR and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) protein were evaluated by western-blot assay...
December 2017: Oncology Letters
https://www.readbyqxmd.com/read/29344229/preparation-and-characterization-of-the-adriamycin-loaded-amphiphilic-chitosan-nanoparticles-and-their-application-in-the-treatment-of-liver-cancer
#20
Chang-Hua Kou, Jin Han, Xi-Lin Han, Hui-Jie Zhuang, Zi-Ming Zhao
In the present study, two nanoparticles including lactose myristoyl carboxymethyl chitosan (LMCC) and algal polysaccharide myristoyl carboxymethyl chitosan (AMCC), were obtained for hepatic-targeted Adriamycin (ADM) drug delivery systems. ADM was successfully loaded into the LMCC or AMCC nanoparticle by dialysis. The release function and liver targeting of the nanoparticles was explored, and it was revealed that ADM release from the nanoparticles was greatest at acidic pH 5.5. ADM-conjugated nanoparticles were readily taken up by HU7 human hepatocellular carcinoma cells, relative to HT22 mouse hippocampal neuron cells in vitro...
December 2017: Oncology Letters
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