Search results for "Toxic"
showing 10 items of 6968 documents
Upgrading HepG2 cells with adenoviral vectors that encode drug-metabolizing enzymes: application for drug hepatotoxicity testing.
2016
Drug attrition rates due to hepatotoxicity are an important safety issue considered in drug development. The HepG2 hepatoma cell line is currently being used for drug-induced hepatotoxicity evaluations, but its expression of drug-metabolizing enzymes is poor compared with hepatocytes. Different approaches have been proposed to upgrade HepG2 cells for more reliable drug-induced liver injury predictions. Areas covered: We describe the advantages and limitations of HepG2 cells transduced with adenoviral vectors that encode drug-metabolizing enzymes for safety risk assessments of bioactivable compounds. Adenoviral transduction facilitates efficient and controlled delivery of multiple drug-metab…
Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems
2018
Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiov…
A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC …
2019
Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of alter…
Nickel toxicity in P. lividus embryos: Dose dependent effects and gene expression analysis.
2018
Abstract Many industrial activities release Nickel (Ni) in the environment with harmful effects for terrestrial and marine organisms. Despite many studies on the mechanisms of Ni toxicity are available, the understanding about its toxic effects on marine organisms is more limited. We used Paracentrotus lividus as a model to analyze the effects on the stress pathways in embryos continuously exposed to different Ni doses, ranging from 0.03 to 0.5 mM. We deeply examined the altered embryonic morphologies at 24 and 48 h after Ni exposure. Some different phenotypes have been classified, showing alterations at the expenses of the dorso-ventral axis as well as the skeleton and/or the pigment cells…
Coexposure to sulfamethoxazole and cadmium impairs development and attenuates transcriptional response in sea urchin embryo
2017
Abstract Among sulfonamides, sulfamethoxazole represents one of the most widely employed. A considerable amount of sulfamethoxazole is introduced into the marine environment after utilization in aquaculture. The cytotoxicity of sulfamethoxazole relies mainly on arylhydroxylamine metabolites and it is associated with the production of reactive oxygen species. Cadmium represents a metal largely employed in several anthropic activities and it is toxic for all living organisms even at low concentrations. Since it is not degraded, cadmium irreversibly accumulates into cells. In order to understand the mechanisms of response to changes in the chemical environment, we investigated by light microsc…
Bioequivalence decision for nanoparticular iron complex drugs for parenteral administration based on their disposition
2017
Although parenteral iron products have been established to medicinal use decades before, their structure and pharmacokinetic properties are not fully characterized yet. With its' second reflection paper on intravenous iron-based nano-colloidal products (EMA/CHMP/SWP/620008/2012) the European Medicine Agency provided an extensive catalogue of methods for quality, non-clinical and pharmacokinetic studies for the comparison of nano-sized iron products to an originator (EMA, 2015). For iron distribution studies, the reflection paper assumed the use of rodents. In our tests, we used a turkey fetus model to investigate time dependent tissue concentrations in pharmacological and toxicological rele…
Retene causes multifunctional transcriptomic changes in the heart of rainbow trout (Oncorhynchus mykiss) embryos
2015
Fish are particularly sensitive to aryl hydrocarbon receptor (AhR)-mediated developmental toxicity. The molecular mechanisms behind these adverse effects have remained largely unresolved in salmonids, and for AhR-agonistic polycyclic aromatic hydrocarbons (PAHs). This study explored the cardiac transcriptome of rainbow trout (Oncorhynchus mykiss) eleuteroembryos exposed to retene, an AhR-agonistic PAH. The embryos were exposed to retene (nominal concentration 32 μg/L) and control, their hearts were collected before, at and after the onset of the visible signs of developmental toxicity, and transcriptomic changes were studied by microarray analysis. Retene up- or down-regulated 122 genes. Th…
Array-based molecular karyotyping in 115 VATER/VACTERL and VATER/VACTERL-like patients identifies disease-causing copy number variations
2017
Background The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CF): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia, renal malformations (R), and limb defects (L). Patients presenting with at least three CFs are diagnosed as having VATER/VACTERL association while patients presenting with only two CFs are diagnosed as having VATER/VACTERL-like phenotypes. Recently, rare causative copy number variations (CNVs) have been identified in patients with VATER/VACTERL association and VATER/VACTERL-like phenotypes. Methods To detect further causative CNVs we perfor…
Targeting CD52 does not affect murine neuron and microglia function.
2020
The humanized anti-CD52 antibody alemtuzumab is successfully used in the treatment of multiple sclerosis (MS) and is thought to exert most of its therapeutic action by depletion and repopulation of mainly B and T lymphocytes. Although neuroprotective effects of alemtuzumab have been suggested, direct effects of anti-CD52 treatment on glial cells and neurons within the CNS itself have not been investigated so far. Here, we show CD52 expression in murine neurons, astrocytes and microglia, both in vitro and in vivo. As expected, anti CD52-treatment caused profound lymphopenia and improved disease symptoms in mice subjected to experimental autoimmune encephalomyelitis (EAE). CD52 blockade also …
Gatekeeper role of brain antigen‐presenting CD11c + cells in neuroinflammation
2015
Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigen-presenting cells, dendritic cells. Applying intravital two-photon microscopy, we demonstrate the gatekeeper function of CNS professional antigen-presenting CD11c(+) cells, which preferentially interact with Th17 cells. IL-17 expression correlates with expression of GM-CSF by T cells and with accumulation of CNS CD11c(+) cells. These CD11c(+) cells are organized in perivascular clusters…