scholarly journals Characterization of Fibrous Wollastonite NYAD G in View of Its Use as Negative Standard for In Vitro Toxicity Tests

Minerals ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1378
Author(s):  
Dario Di Giuseppe ◽  
Valentina Scognamiglio ◽  
Daniele Malferrari ◽  
Luca Nodari ◽  
Luca Pasquali ◽  
...  
Keyword(s):  
Biological Response ◽  
Toxicity Tests ◽  
In Vitro Toxicity ◽  
In Vitro Tests ◽  
In Vivo Models ◽  
Mineral Fibre ◽  
In Vivo Testing ◽  
Positive Controls

Today, despite considerable efforts undertaken by the scientific community, the mechanisms of carcinogenesis of mineral fibres remain poorly understood. A crucial role in disclosing the mechanisms of action of mineral fibres is played by in vitro and in vivo models. Such models require experimental design based on negative and positive controls. Commonly used positive controls are amosite and crocidolite UICC standards, while negative controls have not been identified so far. The extensive characterisation and assessment of toxicity/pathogenicity potential carried out in this work indicate that the commercial fibrous wollastonite NYAD G may be considered as a negative standard control for biological and biomedical tests involving mineral fibres. Preliminary in vitro tests suggest that wollastonite NYAD G is not genotoxic. This material is nearly pure and is characterized by very long (46.6 µm), thick (3.74 µm) and non-biodurable fibres with a low content of metals. According to the fibre potential toxicity index (FPTI) model, wollastonite NYAD G is an inert mineral fibre that is expected to exert a low biological response during in vitro/in vivo testing.

An Innovative Ex Vivo Vascular Bioreactor as Comprehensive Tool to Study the Behavior of Native Blood Vessels Under Physiologically Relevant Conditions

2019 ◽  
Vol 2 (4) ◽  
Author(s):  
Noemi Vanerio ◽  
Marco Stijnen ◽  
Bas A. J. M. de Mol ◽  
Linda M. Kock
Keyword(s):  
Shear Stress ◽  
Blood Vessels ◽  
Ultrasound Imaging ◽  
Ex Vivo ◽  
Biological Response ◽  
Vessel Diameter ◽  
Tissue Growth ◽  
In Vivo Models

Abstract Ex vivo systems represent important models to study vascular biology and to test medical devices, combining the advantages of in vitro and in vivo models such as controllability of parameters and the presence of biological response, respectively. The aim of this study was to develop a comprehensive ex vivo vascular bioreactor to long-term culture and study the behavior of native blood vessels under physiologically relevant conditions. The system was designed to allow for physiological mechanical loading in terms of pulsatile hemodynamics, shear stress, and longitudinal prestretch and ultrasound imaging for vessel diameter and morphology evaluation. In this first experience, porcine carotid arteries (n = 4) from slaughterhouse animals were cultured in the platform for 10 days at physiological temperature, CO2 and humidity using medium with blood-mimicking viscosity, components, and stability of composition. As expected, a significant increase in vessel diameter was observed during culture. Flow rate was adjusted according to diameter values to reproduce and maintain physiological shear stress, while pressure was kept physiological. Ultrasound imaging showed that the morphology and structure of cultured arteries were comparable to in vivo. Histological analyses showed preserved endothelium and extracellular matrix and neointimal tissue growth over 10 days of culture. In conclusion, we have developed a comprehensive pulsatile system in which a native blood vessel can be cultured under physiological conditions. The present model represents a significant step toward ex vivo testing of vascular therapies, devices, drug interaction, and as basis for further model developments.

scholarly journals Formulation of Improved Traditional Drugs against virulent species of Salmonella spp in Benin: assessment of the properties from Uvaria chamae, Lantana camara and Phyllantus amarus in Benin, West Africa

2019 ◽  
Author(s):  
Boris LEGBA ◽  
Victorien DOUGNON ◽  
Carène GBAGUIDI ◽  
Alidah ANIAMBOSSOU ◽  
Esther DEGUENON ◽  
...  
Keyword(s):  
Aqueous Extract ◽  
Bacterial Load ◽  
Scientific Data ◽  
Lantana Camara ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
Post Inoculation ◽  
Salmonella Spp

Abstract Background Uvaria chamae (Annonaceae), Phyllantus amarus (Phyllantaceae) and Lantana camara (Verbenaceae) are empirically alleged to be used as Beninese medicinal plants in the treatment of salmonellosis. This study aimed to produce scientific data on in vitro and in vivo efficacy of Uvaria chamae, Lantana camara and Phyllantus amarus on multiresistant Salmonella spp isolated in Benin.Results After in vitro tests on aqueous and ethanolic extracts of Uvaria chamae, Lantana camara and Phyllantus amarus , only the aqueous extract of Uvaria chamae (leaves) showed the best anti- Salmonella ’s activity. It has been used for the following experiments. The induction of salmonellosis revealed 9.0 10 8 CFU/ml was optimal concentration for triggering and maintaining the symptoms in chicks. This infective concentration has been used for in vivo assessment. 24 hours post inoculation later, the symptoms of salmonellosis (wet cloaca, diarrhea stool and somnolence) were observed in infected groups. After seven days of treatment, the rate of reduction of bacterial load at 100 mg / L, 200 mg / L, 400 mg / L of this extract was 85%, 52.38% and 98% respectively in the chicks groups infected with Salmonella Typhimurium ATCC 14028. About the groups infected with Salmonella spp (virulent strain), the rate of reduction of bacterial load at 100 mg / L, 200 mg / L, 400 mg / L of this extract was 0%, 98.66% and 99.33%. The toxicity tests did not show any significant effect of the Uvaria chamae ’s extract on the biochemical and hematological parameters of the chicks.Conclusion The aqueous extract of Uvaria chamae is active in vitro and in vivo on multiresistant strains of Salmonella spp . This plant is a good candidate for the development of an improved traditional medicine for the management of salmonellosis.

The Multi-Kinase Inhibitor TG02 targets CD34+CD38-CD123+ AML Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1823-1823
Author(s):  
Monica Pallis ◽  
Francis Burrows ◽  
Nigel H. Russell
Keyword(s):  
Kinase Inhibitor ◽  
In Vitro Toxicity ◽  
The Novel ◽  
In Vivo Models ◽  
Erk Activation ◽  
Akt Phosphorylation ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors

Abstract Abstract 1823 In clinical trials, FLT3 inhibitors are reported to kill circulating AML blasts, but the bone marrow is protected. We have previously reported that niche-like conditions (fibronectin and a cytokine cocktail) significantly reduced the in vitro toxicity of the FLT3 inhibitor AG1296 to AML cells. Moreover, the toxicity of AG1296 to the chemoresistant leukaemic CD34+CD38-CD123+ subset was completely abolished under niche-like conditions. The novel multi-kinase inhibitor TG02 has selectivity against cell cycle and transcriptional CDKs and JAK2 as well as FLT3. TG02 has efficacy in in vivo models and induces apoptosis in primary AML cells. We have now evaluated its in vitro toxicity under niche-like conditions in bulk AML cells and in the CD34+CD38-CD123+ subset. In a cohort of six FLT3-ITD and five FLT3-wildtype samples, 100nM TG02 induced decreases of 30% in bulk cells and 32% in CD34+CD38-CD123+ cells, whereas AG1296 (5μM) induced a median 21% decrease in bulk cells under niche-like conditions but a 0% decrease in CD34+CD38-CD123+ cells. Lestaurtinib, sorafenib and sunitinib were used as comparators (all at 100 nM) and induced, respectively, 13%, 4% and 13% decrease in bulk cells and 10%, 0% and 8% decrease in CD34+CD38-CD123+ cells. FLT3 wildtype as well as ITD samples were targeted. In order to establish the molecular pathways involved in niche-mediated chemoresistance and its reversal, we treated primary AML samples with TG02 or AG1296 for 3 hours in the presence and absence of niche proteins; we measured activating phosphorylations of STAT3 (tyr705), STAT5 (tyr694), ERK1/2 (thr202/tyr404) and AKT(ser473). Basal levels of activating phosphorylations were generally higher in the bulk cells than the CD34+CD38-CD123+ cells, possibly reflecting the increased quiescence of the latter subset. STAT3, STAT5 and ERK1/2 phosphorylation were reduced by TG02 to a slightly greater degree than by AG1296 in bulk cells. However, in CD34+CD38-CD123+ cells this contrast was enhanced, such that AG1296 was ineffective, whereas TG02 was at least as effective as in bulk cells. Niche-like conditions induced an increase in phosphorylation of STAT5, but not of the other proteins tested. TG02 reduced this to basal levels in both bulk cells and CD34+CD38-CD123+ cells. AG1296 partially blocked niche-induced STAT5 phosphorylation in bulk cells, but not in CD34+CD38-CD123+ cells. It had no effect on ERK signalling. AKT phosphorylation was not informative. In conclusion, TGO2 is more cytotoxic than comparatively selective FLT3 inhibitors towards CD34+CD38-CD123+ AML cells as well as bulk cells under niche conditions and the toxicity is associated with downregulation of STAT3, STAT5 and ERK activation. Disclosures: Pallis: Tragara Pharmaceuticals: Research Funding. Burrows:Tragara Pharmaceuticals: Employment.

The potential toxicological insights about the anti-HIV drug azidothymidine-derived monoselenides in human leukocytes: Toxicological insights of new selenium-azidothymidine analogs

2016 ◽  
Vol 36 (9) ◽  
pp. 910-918 ◽  
Author(s):  
DOC Mariano ◽  
D de Souza ◽  
DF Meinerz ◽  
J Allebrandt ◽  
AF de Bem ◽  
...  
Keyword(s):  
Antioxidant Properties ◽  
Damage Index ◽  
Human Leukocyte ◽  
In Vitro Toxicity ◽  
Organoselenium Compounds ◽  
In Vivo Models ◽  
Human Leukocytes ◽  
Anti Hiv

Acquired immunodeficiency syndrome (AIDS) is a worldwide disease characterized by impairments of immune function. AIDS can be associated with oxidative stress (OS) that can be linked to selenium (Se) deficiency. Se is fundamental for the synthesis of selenoproteins, such as glutathione peroxidase and thioredoxin reductase. These enzymes catalyze the decomposition of reactive oxygen species and contribute to maintain equilibrium in cell redox status. Literature data indicate that organoselenium compounds, such as ebselen and diphenyl diselenide, have antioxidant properties in vitro and in vivo models associated with OS. Nevertheless, selenocompounds can also react and oxidize thiols groups, inducing toxicity in mammals. Here, we tested the potential cytotoxic and genotoxic properties of six analogs of the prototypal anti-HIV drug azidothymidine (AZT) containing Se (5′-Se-(phenyl)zidovudine; 5′-Se-(1,3,5-trimethylphenyl)zidovudine; 5′-Se-(1-naphtyl)zidovudine; 5′-Se-(4-chlorophenyl)zidovudine) (C4); 5′-Se-(4-methylphenyl)zidovudine (C5); and 5′-(4-methylbenzoselenoate)zidovudine). C5 increased the rate of dithiothreitol oxidation (thiol oxidase activity) and C2-C4 and C6 (at 100 µM) increased DNA damage index (DI) in human leukocytes. Moreover, C5 (200 µM) decreased human leukocyte viability to about 50%. Taken together, these results indicated the low in vitro toxicity in human leukocytes of some Se-containing analogs of AZT.

Assessment of the potential health hazard of fibrous glaucophane

2020 ◽  
Author(s):  
Dario Di Giuseppe ◽  
Alessandro Gualtieri ◽  
Alessandro Zoboli ◽  
Monica Filaferro ◽  
Giovanni Vitale ◽  
...  
Keyword(s):  
Health Hazard ◽  
Toxicity Tests ◽  
International Agency ◽  
Potential Toxicity ◽  
Potential Health ◽  
Franciscan Complex ◽  
Mineral Fibre ◽  
Potential Health Hazard

<p>The widespread concern on the environmental hazards and public health issues related to exposure to respirable dusts from naturally occurring asbestos (NOA) in principle should also apply to deposits of mineral fibres other than the currently regulated six asbestos minerals. Recent studies highlight that glaucophane can assume a fibrous habit resembling the regulated amphibole asbestos minerals. Glaucophane, sometimes occurring in a fibrous habit, is a major mineral component of blueschist rocks of the Franciscan Complex, USA. Recently, fibrous blueschist occurrences within the Franciscan Complex were being excavated in California for construction purposes (<em>e.g.</em>, the Calaveras Dam Replacement Project) and concern existed that the dust generated by the excavation activities might potentially expose workers and the general public to health risks. For this reason, fibrous glaucophane (Gla) was considered to represent a potential health hazard as NOA by the dam owner, the San Francisco Public Utilities Commission, though an evaluation of the potential health hazard of this mineral fibre was not mandatory per local state and federal regulations. To fill this gap, the potential toxicity/pathogenicity of Gla from the Franciscan Complex has been assessed using the fibre potential toxicity model (FPTI) model and specific <em>in vitro</em> toxicity tests. FPTI is an analytical tool to predict the toxicity/pathogenicity of minerals fibers, based on physical/chemical and morphological parameters that induce biochemical mechanisms responsible for <em>in vivo</em> adverse effects. This model delivers an FPTI index aimed at ranking the toxicity and pathogenicity of a mineral fibre. Compared to asbestos minerals, the FPTI of Gla is considerably higher than that of chrysotile, comparable to that of tremolite and lower than that of crocidolite. Biological responses of cultured human lung cells (THP-1 and Met-5A) following 24 and 48h of exposure to different doses of Gla (25, 50 and 100 µg/mL), have been determined by Alamar Blue viability, Extra-cellular lactate dehydrogenase (LDH) and Comet assays. Generation of reactive oxygen species (ROS) has been evaluated performing the luminescent ROS-Glo™ assay. Crocidolite UICC asbestos (100 µg/mL) was also tested for comparison. Results of in vitro tests showed that Gla may induce a decrease in cell viability and an increase in LDH release in tested cell cultures in a concentration dependent mode. Overall, the rank of the investigated fibres in increasing order of cytotoxicity is: Gla (25 μg/mL) < Gla (50 μg/mL) < crocidolite (50 μg/mL) < Gla (100 μg/mL). For both the cells lines, Gla was able to induce DNA damage. Moreover, it was found that Gla can induce the formation of ROS. The chemical-structural features and biological reactivity of Gla confirm that this mineral fibre is a toxic agent. Although Gla induced lower toxic effects compared to the carcinogenic crocidolite, the inhalation of its fibres may be hypothetically responsible for the development of lung diseases. For a conclusive understanding of the mechanisms of the cellular/tissues responses to fibrous glaucophane, <em>in vivo</em> animal tests should be performed and compared to our outcome to stimulate a critical evaluation and a classification by the International Agency for Research on Cancer (IARC).</p>

scholarly journals Predicting and Testing Bioavailability of Magnesium Supplements

Nutrients ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1663 ◽  
Author(s):  
Laura Blancquaert ◽  
Chris Vervaet ◽  
Wim Derave
Keyword(s):  
Serum Magnesium ◽  
Area Under The Curve ◽  
In Vitro Tests ◽  
In Vitro Test ◽  
Beneficial Effects ◽  
Dissolution Tests ◽  
Acute Ingestion ◽  
In Vivo Testing

Despite the presumption of the beneficial effects of magnesium supplementation, little is known about the pharmacokinetics of different magnesium formulations. We aimed to investigate the value of two in vitro approaches to predict bioavailability of magnesium and to validate this in subsequent in vivo testing. In vitro assessment of 15 commercially available magnesium formulations was performed by means of a Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) and by dissolution tests. Two magnesium formulations with contrasting bioavailability prediction from both in vitro tests (best vs. worst) were selected for in vivo testing in 30 subjects. In vivo bioavailability was compared following one acute ingestion by monitoring blood magnesium concentrations up to 6 h following intake. The in vitro tests showed a very wide variation in absorption and dissolution of the 15 magnesium products. In the in vivo testing, a significant different serum magnesium absorption profile was found up to 4 h following supplement ingestion for the two supplements with opposing in vitro test results. Moreover, maximal serum magnesium increase and total area under the curve were significantly different for both supplements (+6.2% vs. +4.6% and 6.87 vs. 0.31 mM.min, respectively). Collectively, poor bioaccessibility and bioavailability in the SHIME model clearly translated into poor dissolution and poor bioavailability in vivo. This provides a valid methodology for the prediction of in vivo bioavailability and effectiveness of micronutrients by specific in vitro approaches.

Endocrine Disruptors: A Critical Review of In Vitro and In Vivo Testing Strategies for Assessing Their Toxic Hazard to Humans

2000 ◽  
Vol 28 (1) ◽  
pp. 81-118 ◽  
Author(s):  
Robert D. Combes
Keyword(s):  
Endocrine Disruptors ◽  
Human Exposure ◽  
Mechanisms Of Action ◽  
Environmental Chemicals ◽  
Toxicity Tests ◽  
In Vitro Tests ◽  
Wide Range ◽  
The Us

Currently, there is much concern that a wide range of both synthetic and naturally occurring environmental chemicals can act as endocrine disruptors (EDs), and can adversely affect humans and wildlife. Many in vivo and in vitro tests have been proposed for screening EDs, and several regulatory agencies, including the US Environmental Protection Agency (EPA), have recommended tier-testing schemes. Unfortunately, most of the proposed toxicity tests have substantial problems, including non-specificity and lack of reproducibility. There is also uncertainty concerning their relevance for generating useful hazard data for risk assessment purposes, in view of the diversity of the possible ED mechanisms of action (for example, receptor binding, steroidogenesis and modulation of the homeostatic processes which regulate endogenous responses to hormones). Moreover, most of the suggested test methods have yet to be validated according to internationally accepted criteria, although the OECD and the US EPA have defined tests for validation, and an interlaboratory “prevalidation” exercise has been initiated by the OECD. All this is compounded by the lack of information regarding human exposure levels to EDs, and a lack of direct evidence for a causal link between exposure and the development of adverse human health effects. In addition, the regulatory testing of EDs has important negative implications for animal welfare, as some of the proposed in vivo tests require large group sizes of animals and stressful procedures. From a detailed analysis of the available published literature, it is concluded that it is impossible to assess the relative values of currently available in vitro and in vivo toxicity tests for EDs, or to recommend any test or test battery. Any plans for the widespread testing of EDs are therefore premature and might be unnecessary, at least for detecting possible human effects. Several recommendations are made for rectifying this unsatisfactory situation, including the postponement of screening programmes pending: a) more information on human exposure; b) further details of the mechanisms of action of EDs; and c) the development of improved tests, followed by their proper scientific validation.

Molecular Targets and Early Response Biomarkers for the Prediction of Developmental Toxicity In Vitro

2007 ◽  
Vol 35 (3) ◽  
pp. 335-342 ◽  
Author(s):  
Michael Stigson ◽  
Kim Kultima ◽  
Måns Jergil ◽  
Birger Scholz ◽  
Henrik Alm ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Developmental Toxicity ◽  
Molecular Targets ◽  
Toxicity Testing ◽  
Early Response ◽  
In Vitro Tests ◽  
In Vivo Models ◽  
Response Biomarkers

There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead identification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed. An understanding of the mechanisms involved in developmental toxicity may be essential for the validation of in vitro tests. Early response biomarkers — even a single one — could contribute to reducing assay time and facilitating automation. The use of toxicogenomics approaches to study in vitro and in vivo models in parallel may be a powerful tool in defining such mechanisms of action and the molecular targets of toxicity, and also for use in finding possible biomarkers of early response. Using valproic acid as a model substance, the use of DNA microarrays to identify teratogen-responsive genes in cell models is discussed. It is concluded that gene expression in P19 mouse embryocarcinoma cells represents a potentially suitable assay system, which could be readily used in a tiered testing system for developmental toxicity testing.

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