scholarly journals Developmental Neurotoxicity of Environmentally Relevant Pharmaceuticals and Mixtures Thereof in a Zebrafish Embryo Behavioural Test

2021 ◽  
Vol 18 (13) ◽  
pp. 6717
Author(s):  
Alessandro Atzei ◽  
Ingrid Jense ◽  
Edwin P. Zwart ◽  
Jessica Legradi ◽  
Bastiaan J. Venhuis ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Animal Studies ◽  
Zebrafish Embryo ◽  
Cumulative Effect ◽  
Developmental Neurotoxicity ◽  
Limited Information ◽  
Behavioural Phenotype ◽  
Chemically Induced ◽  
Behavioural Test

Humans are exposed daily to complex mixtures of chemical substances via food intake, inhalation, and dermal contact. Developmental neurotoxicity is an understudied area and entails one of the most complex areas in toxicology. Animal studies for developmental neurotoxicity (DNT) are hardly performed in the context of regular hazard studies, as they are costly and time consuming and provide only limited information as to human relevance. There is a need for a combination of in vitro and in silico tests for the assessment of chemically induced DNT in humans. The zebrafish (Danio rerio) embryo (ZFE) provides a powerful model to study DNT because it shows fast neurodevelopment with a large resemblance to the higher vertebrate, including the human system. One of the suitable readouts for DNT testing in the zebrafish is neurobehaviour (stimulus-provoked locomotion) since this provides integrated information on the functionality and status of the entire nervous system of the embryo. In the current study, environmentally relevant pharmaceuticals and their mixtures were investigated using the zebrafish light-dark transition test. Zebrafish embryos were exposed to three neuroactive compounds of concern, carbamazepine (CBZ), fluoxetine (FLX), and venlafaxine (VNX), as well as their main metabolites, carbamazepine 10,11-epoxide (CBZ 10,11E), norfluoxetine (norFLX), and desvenlafaxine (desVNX). All the studied compounds, except CBZ 10,11E, dose-dependently inhibited zebrafish locomotor activity, providing a distinct behavioural phenotype. Mixture experiments with these pharmaceuticals identified that dose addition was confirmed for all the studied binary mixtures (CBZ-FLX, CBZ-VNX, and VNX-FLX), thereby supporting the zebrafish embryo as a model for studying the cumulative effect of chemical mixtures in DNT. This study shows that pharmaceuticals and a mixture thereof affect locomotor activity in zebrafish. The test is directly applicable in environmental risk assessment; however, further studies are required to assess the relevance of these findings for developmental neurotoxicity in humans.

Ultrastructural Changes in Tumor Cells During Human Peripheral Blood Monocyte-Mediated Cytotoxicity

1981 ◽  
Vol 39 ◽  
pp. 452-453
Author(s):  
K. E. Muse ◽  
D. G. Fischer ◽  
H. S. Koren
Keyword(s):  
Target Cell ◽  
Human Peripheral Blood ◽  
Mononuclear Phagocytes ◽  
Ultrastructural Changes ◽  
Target Cells ◽  
Limited Information ◽  
Blood Monocytes ◽  
Tumoricidal Activity ◽  
Activated State

Mononuclear phagocytes, a pluripotential cell line, manifest an array of basic extracellular functions. Among these physiological regulatory functions is the expression of spontaneous cytolytic potential against tumor cell targets.The limited observations on human cells, almost exclusively blood monocytes, initially reported limited or a lack of tumoricidal activity in the absence of antibody. More recently, freshly obtained monocytes have been reported to spontaneously impair the biability of tumor target cells in vitro (Harowitz et al., 1979; Montavani et al., 1979; Hammerstrom, 1979). Although the mechanism by which effector cells express cytotoxicity is poorly understood, discrete steps can be distinguished in the process of cell mediated cytotoxicity: recognition and binding of effector to target cells,a lethal-hit stage, and subsequent lysis of the target cell. Other important parameters in monocyte-mediated cytotoxicity include, activated state of the monocyte, effector cell concentrations, and target cell suseptibility. However, limited information is available with regard to the ultrastructural changes accompanying monocyte-mediated cytotoxicity.

Decellularized bone extracellular matrix in skeletal tissue engineering

2020 ◽  
Vol 48 (3) ◽  
pp. 755-764
Author(s):  
Benjamin B. Rothrauff ◽  
Rocky S. Tuan
Keyword(s):  
Tissue Engineering ◽  
Bone Regeneration ◽  
Tissue Regeneration ◽  
Animal Studies ◽  
Tumor Resection ◽  
Regenerative Capacity ◽  
Skeletal Tissue ◽  
Large Bone

Bone possesses an intrinsic regenerative capacity, which can be compromised by aging, disease, trauma, and iatrogenesis (e.g. tumor resection, pharmacological). At present, autografts and allografts are the principal biological treatments available to replace large bone segments, but both entail several limitations that reduce wider use and consistent success. The use of decellularized extracellular matrices (ECM), often derived from xenogeneic sources, has been shown to favorably influence the immune response to injury and promote site-appropriate tissue regeneration. Decellularized bone ECM (dbECM), utilized in several forms — whole organ, particles, hydrogels — has shown promise in both in vitro and in vivo animal studies to promote osteogenic differentiation of stem/progenitor cells and enhance bone regeneration. However, dbECM has yet to be investigated in clinical studies, which are needed to determine the relative efficacy of this emerging biomaterial as compared with established treatments. This mini-review highlights the recent exploration of dbECM as a biomaterial for skeletal tissue engineering and considers modifications on its future use to more consistently promote bone regeneration.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

Protective Effect of Isothiocyanates from Cruciferous Vegetables on Breast Cancer: Epidemiological and Preclinical Perspectives

2020 ◽  
Vol 20 ◽  
Author(s):  
Suong N.T. Ngo ◽  
Desmond B. Williams
Keyword(s):  
Breast Cancer ◽  
Protective Effect ◽  
Animal Studies ◽  
Cancer Survival ◽  
Breast Cancer Survival ◽  
Human Studies ◽  
In Vitro Studies ◽  
Cochrane Library ◽  
Cruciferous Vegetables

Background: The effect of cruciferous vegetable intake on breast cancer survival is controversial at present. Glucosinolates are the naturally occurring constituents found across the cruciferous vegetables. Isothiocyanates are produced from the hydrolysis of glucosinolates and this reaction is catalysed by the plant-derived enzyme myrosinase. The main isothiocyanates (ITCs) from cruciferous vegetables are sulforaphane, benzyl ITC, and phenethyl ITC, which had been intensively investigated over the last decade for their antibreast cancer effects. Objective: The aim of this article is to systematically review the evidence from all types of studies, which examined the protective effect of cruciferous vegetables and/or their isothiocyanate constituents on breast cancer. Methods: A systematic review was conducted in Pubmed, EMBASE, and the Cochrane Library from inception to 27 April 2020. Peerreviewed studies of all types (in vitro studies, animal studies, and human studies) were selected. Results: The systematic literature search identified 16 human studies, 4 animal studies, and 65 in vitro studies. The effect of cruciferous vegetables and/or their ITCs intake on breast cancer survival was found to be controversial and varied greatly across human studies. Most of these trials were observational studies conducted in specific regions, mainly in the US and China. Substantial evidence from in vitro and animal studies was obtained, which strongly supported the protective effect of sulforaphane and other ITCs against breast cancer. Evidence from in vitro studies showed sulforaphane and other ITCs reduced cancer cell viability and proliferation via multiple mechanisms and pathways. Isothiocyanates inhibited cell cycle, angiogenesis and epithelial mesenchymal transition, as well as induced apoptosis and altered the expression of phase II carcinogen detoxifying enzymes. These are the essential pathways which promote the growth and metastasis of breast cancer. Noticeably, benzyl ITC showed a significant inhibitory effect on breast cancer stem cells, a new dimension of chemoresistance in breast cancer treatment. Sulforaphane and other ITCs displayed anti-breast cancer effects at variable range of concentrations and benzyl isothiocyanate appeared to have a relatively smallest inhibitory concentration IC50. The mechanisms underlying the cancer protective effect of sulforaphane and other ITCs have also been highlighted in this article. Conclusion: Current preclinical evidence strongly supports the role of sulforaphane and other ITCs as potential therapeutic agents for breast cancer, either as adjunct therapy or combined therapy with current anti-breast cancer drugs, with sulforaphane appeared to display the greatest potential.

scholarly journals Optimal Initial Positioning of Chest Tubes to Prevent Retained Hemothorax Using a Novel Steerable Chest Tube With Extendable Infusion Cannula

2021 ◽  
Vol 186 (Supplement_1) ◽  
pp. 324-330
Author(s):  
John B Fortune ◽  
Serena Murphy ◽  
Kimberley Tiller
Keyword(s):  
Chest Tube ◽  
Animal Studies ◽  
Training Session ◽  
Penetrating Trauma ◽  
Pleural Space ◽  
Tube Placement ◽  
Clot Lysis ◽  
Retained Hemothorax ◽  
Tip Position

ABSTRACT Introduction With blunt and penetrating trauma to the chest, warfighters and civilians frequently suffer from punctured lung (pneumothorax) and/or bleeding into the pleural space (hemothorax). Optimal management of this condition requires the rapid placement of a chest tube to evacuate as much of the blood and air as possible. Incomplete drainage of blood leading to retained hemothorax may be the result of the final tube tip position not being in contact with the blood collections. To address this problem, we sought to develop a “steerable” chest tube that could be accurately placed or repositioned into a specific desired position in the pleural space to assure optimal drainage. An integrated infusion cannula was added for the instillation of anticoagulants to maintain tube patency, thrombolytics for clot lysis, and analgesics for pain control if required. Materials and Methods A triple-lumen tube was designed to provide a channel for a pull-wire which was wound around an axle integrated into a small proximal handle and controlled by a ratcheted thumbwheel. Tension on the wire creates an arc on the tube that allows for positioning. In vitro testing focused on the relationship between the tension on the pull-wire and the resultant arc. Two adult cadavers and two anesthetized pigs were used to study the feasibility of accurate tube placement. After a brief training session, providers were asked to place tubes inferiorly along the diaphragm where blood was anticipated to accumulate or at the apex of the lung for pneumothorax. Success was determined with fluoroscopic images and was judged as a tube tip lying in the targeted position. Results The design was prototyped with an extruded polyvinyl chloride multilumen tube and a 3D printed tensioning handle. In vitro studies showed that one turn of the thumbwheel created 70° to 90° of arc of the tube. Cadaver and animal studies showed consistent success in the desired placement of the tube at or near the lateral diaphragm or in the apex. Attempts were also successful by surgical residents with minimal training. Conclusions Initial preliminary studies on a novel steerable chest tube have demonstrated the ability to appropriately position the tube in a desired location. The addition of an extendable cannula will allow for safe clot lysis or maintained tube patency. Additional studies are planned to confirm the benefit of this device in preventing retained hemothorax.

The Use of Biomarkers as Alternatives to Current Animal Tests on Food Chemicals

1998 ◽  
Vol 26 (4) ◽  
pp. 421-480
Author(s):  
Krys Bottrill
Keyword(s):  
Animal Studies ◽  
Developmental Toxicity ◽  
Reproductive Toxicity ◽  
In Vitro Test ◽  
Animal Testing ◽  
Dietary Biomarkers ◽  
Recent Developments ◽  
Mechanistic Basis ◽  
The Three Rs

Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health.

scholarly journals Graphene-Doped Poly (Methyl-Methacrylate) (Pmma) Implants: A Micro-CT and Histomorphometrical Study in Rabbits

2021 ◽  
Vol 22 (3) ◽  
pp. 1441
Author(s):  
Antonio Scarano ◽  
Tiziana Orsini ◽  
Fabio Di Carlo ◽  
Luca Valbonetti ◽  
Felice Lorusso
Keyword(s):  
Methyl Methacrylate ◽  
Dental Implant ◽  
Animal Studies ◽  
White Male ◽  
Biological Response ◽  
Medullary Canal ◽  
Poly Methyl Methacrylate ◽  
Titanium Surfaces ◽  
Dental Applications

Background—the graphene-doping procedure represents a useful procedure to improve the mechanical, physical and biological response of several Polymethyl methacrylate (PMMA)-derived polymers and biomaterials for dental applications. The aim of this study was to evaluate osseointegration of Graphene doped Poly(methyl methacrylate) (GD-PMMA) compared with PMMA as potential materials for dental implant devices. Methods—eighteen adult New Zealand white male rabbits with a mean weight of approx. 3000 g were used in this research. A total of eighteen implants of 3.5 mm diameter and 11 mm length in GD-PMMA and eighteen implants in PMMA were used. The implants were placed into the articular femoral knee joint. The animals were sacrificed after 15, 30 and 60 days and the specimens were evaluated by µCT and histomorphometry. Results—microscopically, all 36 implants, 18 in PMMA and 18 in DG-PMMA were well-integrated into the bone. The implants were in contact with cortical bone along the upper threads, while the lower threads were in contact with either newly formed bone or with marrow spaces. The histomorphometry and µCT evaluation showed that the GP-PMMA and PMMA implants were well osseointegrated and the bone was in direct contact with large portions of the implant surfaces, including the space in the medullary canal. Conclusions—in conclusion, the results suggest that GD-PMMA titanium surfaces enhance osseointegration in rabbit femurs. This encourages further research to obtain GD-PMMA with a greater radiopacity. Also, further in vitro and vivo animal studies are necessary to evaluate a potential clinical usage for dental implant applications.

scholarly journals Occupational Exposure to Carbon Nanotubes and Carbon Nanofibres: More Than a Cobweb

Nanomaterials ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 745
Author(s):  
Enrico Bergamaschi ◽  
Giacomo Garzaro ◽  
Georgia Wilson Jones ◽  
Martina Buglisi ◽  
Michele Caniglia ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Animal Studies ◽  
Chemical Properties ◽  
Biological Behavior ◽  
Cross Sectional ◽  
Carbon Nanofibres ◽  
Material Entity ◽  
Cross Sectional Design

Carbon nanotubes (CNTs) and carbon nanofibers (CNFs) are erroneously considered as singular material entities. Instead, they should be regarded as a heterogeneous class of materials bearing different properties eliciting peculiar biological outcomes both in vitro and in vivo. Given the pace at which the industrial production of CNTs/CNFs is increasing, it is becoming of utmost importance to acquire comprehensive knowledge regarding their biological activity and their hazardous effects in humans. Animal studies carried out by inhalation showed that some CNTs/CNFs species can cause deleterious effects such as inflammation and lung tissue remodeling. Their physico-chemical properties, biological behavior and biopersistence make them similar to asbestos fibers. Human studies suggest some mild effects in workers handling CNT/CNF. However, owing to their cross-sectional design, researchers have been as yet unable to firmly demonstrate a causal relationship between such an exposure and the observed effects. Estimation of acceptable exposure levels should warrant a proper risk management. The aim of this review is to challenge the conception of CNTs/CNFs as a single, unified material entity and prompt the establishment of standardized hazard and exposure assessment methodologies able to properly feeding risk assessment and management frameworks.

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