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Articles de revues sur le sujet "Embryo, Disease Model"
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Simoni, Michael K., Sydnie Swanson, Monica Mainigi et Kellie Jurado. « 22732 Impact of Type-I Interferon Manipulation During Embryo Implantation and Placentation ». Journal of Clinical and Translational Science 5, s1 (mars 2021) : 94–95. http://dx.doi.org/10.1017/cts.2021.644.
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ABSTRACT IMPACT: This research will promote understanding the role of the Type-I Interferon signaling pathway during embryo implantation, potentially leading to a new diagnostic or treatment target in early pregnancy failure. OBJECTIVES/GOALS: Studies suggest interferon signaling regulation is tightly balanced between physiologic and pathophysiologic growth in early pregnancy. We propose to determine the impact of interferon-mediated inflammation on embryo implantation and early pregnancy failure in normal conditions and chronic inflammatory diseases in a novel mixed-mouse model. METHODS/STUDY POPULATION: To probe the role of type-I interferons (IFNs) in implantation, we will utilize a mouse model and non-surgically transfer both Ifnar1-/- and Ifnar1-/+ embryos into an immune-competent pseudopregnant wild-type female recipient. This will allow analysis of a litter with distinct genotypes within the same, immune-competent, uterine environment. Type-I IFN stimulation will be systemically induced with Poly-(I:C) at various time points around implantation. A similar approach will be used in mouse models of chronic inflammatory disease states associated with early pregnancy loss (e.g. systemic lupous erythematous). With this model, we will be able to control for deficiencies in maternal immune response to specifically determine the embryonic response to inflammation during implantation and development. RESULTS/ANTICIPATED RESULTS: We anticipate the Ifnar1-/+ embryos - those able to respond to Type-I IFN - and their surrounding implantation sites will exhibit more maternal-fetal barrier dysfunction in the form of impaired trophoblast fusion, improper formation of the microvascular architecture, and increased permeability of the maternal-fetal barrier, compared to embryos unable to respond to IFN. We will also conduct similar analyses in mouse models of chronic inflammatory diseases. We hypothesize these mice to have baseline endometrial inflammation that stimulated the IFN-pathway in IFN-capable embryos, producing breakdown of the maternal-fetal barrier. In these mice, we predict Ifnar1-/- embryos will show improved molecular outcomes when compared to Ifnar1-/+ embryos, and thus improved associated pregnancy outcomes. DISCUSSION/SIGNIFICANCE OF FINDINGS: This work can insight into the immunological mechanisms that govern embryo implantation and early placentation. This could provide more pointed means for management and intervention of early pregnancy failure and/or disease states that are commonly associated with poor reproductive outcomes.
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Kumar, Akash, Kate Im, Milena Banjevic, Pauline C. Ng, Tate Tunstall, Geronimo Garcia, Luisa Galhardo et al. « Whole-genome risk prediction of common diseases in human preimplantation embryos ». Nature Medicine 28, no 3 (mars 2022) : 513–16. http://dx.doi.org/10.1038/s41591-022-01735-0.
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AbstractPreimplantation genetic testing (PGT) of in-vitro-fertilized embryos has been proposed as a method to reduce transmission of common disease; however, more comprehensive embryo genetic assessment, combining the effects of common variants and rare variants, remains unavailable. Here, we used a combination of molecular and statistical techniques to reliably infer inherited genome sequence in 110 embryos and model susceptibility across 12 common conditions. We observed a genotype accuracy of 99.0–99.4% at sites relevant to polygenic risk scoring in cases from day-5 embryo biopsies and 97.2–99.1% in cases from day-3 embryo biopsies. Combining rare variants with polygenic risk score (PRS) magnifies predicted differences across sibling embryos. For example, in a couple with a pathogenic BRCA1 variant, we predicted a 15-fold difference in odds ratio (OR) across siblings when combining versus a 4.5-fold or 3-fold difference with BRCA1 or PRS alone. Our findings may inform the discussion of utility and implementation of genome-based PGT in clinical practice.
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Feuer, Sky K., Xiaowei Liu, Annemarie Donjacour, Wingka Lin, Rhodel K. Simbulan, Gnanaratnam Giritharan, Luisa Delle Piane et al. « Use of a Mouse In Vitro Fertilization Model to Understand the Developmental Origins of Health and Disease Hypothesis ». Endocrinology 155, no 5 (1 mai 2014) : 1956–69. http://dx.doi.org/10.1210/en.2013-2081.
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The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases such as diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertility, disturbs homeostasis and affects long-term growth and metabolism. To address this controversy, we have assessed the effects of in vitro fertilization (IVF) on postnatal physiology in mice. We demonstrate that IVF and embryo culture, even under conditions considered optimal for mouse embryo culture, alter postnatal growth trajectory, fat accumulation, and glucose metabolism in adult mice. Unbiased metabolic profiling in serum and microarray analysis of pancreatic islets and insulin sensitive tissues (liver, skeletal muscle, and adipose tissue) revealed broad changes in metabolic homeostasis, characterized by systemic oxidative stress and mitochondrial dysfunction. Adopting a candidate approach, we identify thioredoxin-interacting protein (TXNIP), a key molecule involved in integrating cellular nutritional and oxidative states with metabolic response, as a marker for preimplantation stress and demonstrate tissue-specific epigenetic and transcriptional TXNIP misregulation in selected adult tissues. Importantly, dysregulation of TXNIP expression is associated with enrichment for H4 acetylation at the Txnip promoter that persists from the blastocyst stage through adulthood in adipose tissue. Our data support the vulnerability of preimplantation embryos to environmental disturbance and demonstrate that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness. This study has wide clinical relevance and underscores the importance of continued follow-up of IVF-conceived offspring.
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Rosner, Margit, Manuel Reithofer, Dieter Fink et Markus Hengstschläger. « Human Embryo Models and Drug Discovery ». International Journal of Molecular Sciences 22, no 2 (11 janvier 2021) : 637. http://dx.doi.org/10.3390/ijms22020637.
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For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery.
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Rosner, Margit, Manuel Reithofer, Dieter Fink et Markus Hengstschläger. « Human Embryo Models and Drug Discovery ». International Journal of Molecular Sciences 22, no 2 (11 janvier 2021) : 637. http://dx.doi.org/10.3390/ijms22020637.
Texte intégralRésumé :
For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery.
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Bowley, George, Timothy JA Chico, Jovana Serbanovic-Canic et Paul C. Evans. « Quantifying endothelial cell proliferation in the zebrafish embryo ». F1000Research 10 (11 octobre 2021) : 1032. http://dx.doi.org/10.12688/f1000research.73130.1.
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Introduction: Endothelial cell (EC) proliferation is a fundamental determinant of vascular development and homeostasis, and contributes to cardiovascular disease by increasing vascular permeability to blood-borne lipoproteins. Rodents have been traditionally used to analyse EC proliferation mechanisms in vascular health and disease; however, alternative models such as the zebrafish embryo allow researchers to conduct small scale screening studies in a physiologically relevant vasculature whilst reducing the use of mammals in biomedical research. In vitro models of EC proliferation are valuable but do not fully recapitulate the complexity of the in vivo situation. Several groups have used zebrafish embryos for vascular biology research because they offer the advantages of an in vivo model in terms of complexity but are also genetically manipulable and optically transparent. Methods: Here we investigated whether zebrafish embryos can provide a suitable model for the study of EC proliferation. We explored the use of antibody, DNA labelling, and time-lapse imaging approaches. Results: Antibody and DNA labelling approaches were of limited use in zebrafish due to the low rate of EC proliferation combined with the relatively narrow window of time in which they can label proliferating nuclei. By contrast, time-lapse imaging of fluorescent proteins localised to endothelial nuclei was a sensitive method to quantify EC proliferation in zebrafish embryos. Discussion: We conclude that time-lapse imaging is suitable for analysis of endothelial cell proliferation in zebrafish, and that this method is capable of capturing more instances of EC proliferation than immunostaining or cell labelling alternatives. This approach is relevant to anyone studying endothelial cell proliferation for screening genes or small molecules involved in EC proliferation. It offers greater biological relevance than existing in vitro models such as HUVECs culture, whilst reducing the overall number of animals used for this type of research.
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Swanson, W. F., H. L. Bateman, J. Newsom, V. A. Conforti, J. R. Herrick, C. A. Lambo, M. E. Haskins et al. « 55 PROPAGATION OF MULTIPLE CAT HEREDITARY DISEASE MODELS FOLLOWING ASSISTED REPRODUCTION WITH FROZEN SEMEN AND EMBRYOS ». Reproduction, Fertility and Development 24, no 1 (2012) : 139. http://dx.doi.org/10.1071/rdv24n1ab55.
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Domestic cats are invaluable research models for the study of hereditary diseases that affect both cats and humans. By necessity, most cat models are maintained as living populations; however, semen and embryo cryopreservation could provide a cost-effective alternative for model conservation if viable offspring can be readily produced with assisted reproductive techniques such as IVF, embryo transfer (ET) and AI. In our earlier research, semen and IVF-derived embryos representing 24 cat models at 7 veterinary/medical schools were frozen for liquid nitrogen storage. Our objectives in this study were to (1) assess the application of assisted reproduction using frozen semen or embryos for producing pregnancies and viable kittens in several cat models and (2) provide our university collaborators with rederived model offspring. Five cat models (i.e. spinal muscular atrophy, SMA; porphyria, POR; Chediak-Higashi syndrome, CHS; progressive retinal atrophy, PRA; and hypertrophic cardiomyopathy, HCM) were selected for propagation based on investigator research needs. For 3 models (SMA, POR and CHS), semen from affected males, frozen as pellets in Test Egg Yolk medium (with 4% glycerol), was thawed and used to inseminate (5 × 105 motile sperm mL–1) oocytes from eCG/hCG-treated queens. Resulting embryos (2- to 8-cell stage) were transferred laparoscopically (3–5 embryos/recipient) into the oviducts of anestrual queens synchronized with eCG/pLH. For PRA, IVF embryos from affected cats were frozen in 1.5 M ethylene glycol and later thawed for transfer into eCG/pLH-synchronized queens and for HCM, frozen semen from a carrier male was used for laparoscopic oviducal insemination (1 × 106 to 4 × 106 motile sperm/AI) of eCG/pLH-treated females. Ultrasonography was conducted approximately 21 days post-ET or -AI for pregnancy diagnosis. Following IVF with frozen-thawed semen, embryos were produced in all 3 models but overall fertilization success was low (21%, 34/164). All (5/5) recipients became pregnant after ET, giving birth to a total of 11 offspring (6 viable, 5 stillborn). Following frozen ET (PRA), most (3/5) recipients became pregnant with 6 kittens carried to term (3 viable, 3 stillborn), whereas with frozen semen AI (HCM), most (4/7) females conceived with the subsequent birth of 22 kittens (all viable). All surviving offspring (n = 25) for the 5 disease models were distributed to collaborating veterinary schools to reestablish breeding colonies or for ongoing studies. These results indicate that assisted reproduction using frozen semen or embryos may be applied effectively with specific cat models to propagate desired lineages or reestablish research colonies, although some other models have proven more difficult to reproduce. These findings validate our contention that cryopreservation and assisted reproduction may be used to manage and conserve these irreplaceable cat disease models. Funded by NIH grants RR015338, RR02512, HL093603 and HD39888.
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Tobia, Chiara, Daniela Coltrini, Roberto Ronca, Alessandra Loda, Jessica Guerra, Elisa Scalvini, Francesco Semeraro et Sara Rezzola. « An Orthotopic Model of Uveal Melanoma in Zebrafish Embryo : A Novel Platform for Drug Evaluation ». Biomedicines 9, no 12 (10 décembre 2021) : 1873. http://dx.doi.org/10.3390/biomedicines9121873.
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Uveal melanoma is a highly metastatic tumor, representing the most common primary intraocular malignancy in adults. Tumor cell xenografts in zebrafish embryos may provide the opportunity to study in vivo different aspects of the neoplastic disease and its response to therapy. Here, we established an orthotopic model of uveal melanoma in zebrafish by injecting highly metastatic murine B16-BL6 and B16-LS9 melanoma cells, human A375M melanoma cells, and human 92.1 uveal melanoma cells into the eye of zebrafish embryos in the proximity of the developing choroidal vasculature. Immunohistochemical and immunofluorescence analyses showed that melanoma cells proliferate during the first four days after injection and move towards the eye surface. Moreover, bioluminescence analysis of luciferase-expressing human 92.1 uveal melanoma cells allowed the quantitative assessment of the antitumor activity exerted by the canonical chemotherapeutic drugs paclitaxel, panobinostat, and everolimus after their injection into the grafted eye. Altogether, our data demonstrate that the zebrafish embryo eye is a permissive environment for the growth of invasive cutaneous and uveal melanoma cells. In addition, we have established a new luciferase-based in vivo orthotopic model that allows the quantification of human uveal melanoma cells engrafted in the zebrafish embryo eye, and which may represent a suitable tool for the screening of novel drug candidates for uveal melanoma therapy.
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Gregg, K., S. Chen, S. Sadeghieh, T. Guerra, T. Xiang, J. Meredith et I. Polejaeva. « 149 RISK ASSESSMENT OF INFECTIOUS DISEASE TRANSMISSION VIA IN VITRO EMBRYO PRODUCTION USING SOMATIC CELL NUCLEAR TRANSFER ». Reproduction, Fertility and Development 21, no 1 (2009) : 174. http://dx.doi.org/10.1071/rdv21n1ab149.
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Somatic cell nuclear transfer (SCNT) technology is a powerful tool for preservation and propagation of superior genetics of livestock animals. Bovine oocytes derived from abattoirs are usually used in SCNT embryo production. The puncture of the zona pellucida during the nuclear transfer process has raised additional concerns about the risk of disease transmission through application of this new technology. The objective of this study was to use bovine viral diarrhea virus (BVDV) as a model to perform a comprehensive risk assessment on infectious disease transmission in the SCNT system. Thirteen batches of cumulus–oocyte complexes (COC; n = 550) were collected from several abattoirs over 6 months. Two hundred were tested for BVDV before cumulus cell removal. Cumulus cells were removed from the other 350 COC by gentle vortexing in 0.1% hyaluronidase in HEPES-M199 with Hanks’ salts. The cumulus-cell-free oocytes (CFO) were then washed 3 times with FBS-free HEPES-M199 with Hanks’ salts containing penicillin-streptomycin solution (5 μg mL–1). Both COC and CFO were pooled in groups (5/group) and tested for presence of BVDV using sensitive real-time PCR method. Only 2.5% of the COC were BVDV positive and all of the CFO were BVDV negative. Additionally, 293 embryos were produced from 14 different cell lines using the previously described SCNT procedure (Zhou et al. 2008 Mol Reprod Dev. 75, 1281–1289). These embryos were generated using in vitro-matured oocytes collected as 23 different batches over 7 months. The embryos were cultured in vitro to blastocyst stage and then tested for BVDV. All of the 293 SCNT embryos (100%) were BVDV negative. In conclusion, under these SCNT embryo production conditions, a small portion of COC were BVDV positive. However, all CFO and SCNT embryos were BVDV negative. Therefore, the risk of disease transmission using abattoir oocytes and SCNT procedure is relatively low and can be eliminated by using a combination of cumulus cell removal and adequate oocyte washing procedures. F. Arenivas, B. Findeisen, V. Farrar, E. Hwang helped with the SCNT embryo production for this study.
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Posner, Mason, Kelly L. Murray, Matthew S. McDonald, Hayden Eighinger, Brandon Andrew, Amy Drossman, Zachary Haley, Justin Nussbaum, Larry L. David et Kirsten J. Lampi. « The zebrafish as a model system for analyzing mammalian and native α-crystallin promoter function ». PeerJ 5 (27 novembre 2017) : e4093. http://dx.doi.org/10.7717/peerj.4093.
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Previous studies have used the zebrafish to investigate the biology of lens crystallin proteins and their roles in development and disease. However, little is known about zebrafish α-crystallin promoter function, how it compares to that of mammals, or whether mammalian α-crystallin promoter activity can be assessed using zebrafish embryos. We injected a variety of α-crystallin promoter fragments from each species combined with the coding sequence for green fluorescent protein (GFP) into zebrafish zygotes to determine the resulting spatiotemporal expression patterns in the developing embryo. We also measured mRNA levels and protein abundance for all three zebrafish α-crystallins. Our data showed that mouse and zebrafish αA-crystallin promoters generated similar GFP expression in the lens, but with earlier onset when using mouse promoters. Expression was also found in notochord and skeletal muscle in a smaller percentage of embryos. Mouse αB-crystallin promoter fragments drove GFP expression primarily in zebrafish skeletal muscle, with less common expression in notochord, lens, heart and in extraocular regions of the eye. A short fragment containing only a lens-specific enhancer region increased lens and notochord GFP expression while decreasing muscle expression, suggesting that the influence of mouse promoter control regions carries over into zebrafish embryos. The two paralogous zebrafish αB-crystallin promoters produced subtly different expression profiles, with the aBa promoter driving expression equally in notochord and skeletal muscle while the αBb promoter resulted primarily in skeletal muscle expression. Messenger RNA for zebrafish αA increased between 1 and 2 days post fertilization (dpf), αBa increased between 4 and 5 dpf, but αBb remained at baseline levels through 5 dpf. Parallel reaction monitoring (PRM) mass spectrometry was used to detect αA, aBa, and αBb peptides in digests of zebrafish embryos. In whole embryos, αA-crystallin was first detected by 2 dpf, peaked in abundance by 4–5 dpf, and was localized to the eye. αBa was detected in whole embryo at nearly constant levels from 1–6 dpf, was also localized primarily to the eye, and its abundance in extraocular tissues decreased from 4–7 dpf. In contrast, due to its low abundance, no αBb protein could be detected in whole embryo, or dissected eye and extraocular tissues. Our results show that mammalian α-crystallin promoters can be efficiently screened in zebrafish embryos and that their controlling regions are well conserved. An ontogenetic shift in zebrafish aBa-crystallin promoter activity provides an interesting system for examining the evolution and control of tissue specificity. Future studies that combine these promoter based approaches with the expanding ability to engineer the zebrafish genome via techniques such as CRISPR/Cas9 will allow the manipulation of protein expression to test hypotheses about lens crystallin function and its relation to lens biology and disease.
Thèses sur le sujet "Embryo, Disease Model"
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Lima, Amorce. « Bartonella henselae Infection and Host Response in the Zebrafish Embryo Model ». Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5256.
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The Gram-negative bacterium Bartonella henselae (Bh) is an emerging zoonotic pathogen that has been associated with a variety of human diseases including bacillary angiomatosis which is characterized by vasoproliferative tumor-like lesions on the skin and internal organs of some immunosuppressed individuals. Several virulence factors associated with Bartonella-induced pathogenesis have been characterized. However, the study of those virulence factors has been limited to in vitro cell culture systems due to the lack of a practical animal model. Therefore, we wanted to investigate whether the zebrafish embryo (Danio rerio) could be used to model human infection with Bh. We investigated if Bh can mount an infection in zebrafish embryos during their early stage of development. Our data showed that Tg(fli1:egfp)y1 zebrafish embryos supported a sustained Bh infection for 7 days with >10-fold bacterial replication when inoculated in the yolk sac. This was evident by plating of zebrafish homogenates, quantitative PCR, and confocal microscopy analysis. We assessed the interaction of Bh with EC and the phagocytic cells in live embryos by microscopy. Our data showed that aggregates of Bh interact with the endothelium of the embryo vasculature. Evidence showed that Bh recruited phagocytes to the site of infection in the Tg(mpx:GFP)uwm1 embryos. We also wanted to determine the response to infection with Bh. Infected embryos showed evidence of a Bh-induced angiogenic phenotype as well as an increase in expression of genes encoding pro-inflammatory factors and pro-angiogenic markers. A deletion mutant for the entire VirB type IV secretion system (ΔvirB2-11 supported bacterial replication although to a lesser degree compared to the wild type control. However, infection of zebrafish embryos with a deletion mutant in the major adhesin (BadA) resulted in little or no bacterial replication and a diminished pro-angiogenic and pro-inflammatory host response compared to wild type Bh, providing the first evidence that BadA is critical for in vivo infection. Thus, the zebrafish embryo provides the first practical animal model of Bh infection that will facilitate efforts to identify virulence factors and define molecular mechanisms of Bh pathogenesis.
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Khursheed, K. N. « Development of a chick embryo model to study important regulatory domains of human genes implicated in Motor Neurone Disease ». Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3012222/.
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Motor neurone disease refers to a group of neurological disorders that result from progressive degeneration of the motor neurones leading to death from respiratory failure within 3-5 years from the onset of symptoms. Amyotrophic lateral sclerosis (ALS) is one of the most common forms of motor neurone disease, and can be described as entailing the involvement of both upper and lower motor neurones. Usually, the disease is obvious and presents as asymmetrical weakness in the limbs and progressive muscular atrophy. Over the last two decades more than 30 genes have been identified as involved in ALS pathology. These include PARK7 and FUS (Fused in sarcoma) which are the subject of this thesis. FUS is a multifunctional protein that has ubiquitous expression and is involved in different steps of RNA processing such as mRNA and miRNA. 10% of ALS cases are heritable and mutation of the FUS gene is found in 3-5% of familial forms of ALS. Therefore the FUS gene is important for it association as a candidate gene that is postulated to be important for ALS, in addition to various types of cancer. Mutations with FUS gene have been found in autopsy samples from the brain and spinal cord of patients with ALS. Understanding the regulation of FUS gene expression may, therefore, give insights into how its stimulus inducible expression may be associated with neurological disorders. My hypothesis is that the evolutionary conserved regions (ECRs) and primate specific retrotransposons of the SINE-VNTR Alu (SVA) are regulatory domains from the human FUS gene and PARK7 genes. Consequently, the aim of this thesis was to develop an in vivo model to validate their regulation. Comparative genomic analysis was used between distant species, utilizing the ECR browser and UCSC browser to identify conserved regions from the FUS gene. It is demonstrated that ECR and SVA, xviii which can drive reporter gene activity in vitro (in the neuroblastoma cell line), are also capable of driving reporter gene expression in the chick embryo neural tube and brain at embryonic day 5. In conclusion, these identified important ECRs from human FUS gene act as regulatory domains. In addition, the SVAs, representing the most recent retrotransposon to enter the human genome also was showed to have regulatory properties in FUS and PARK7 genes. Furthermore, the thesis demonstrates that these elements regulate gene expression in vitro and in vivo. This supports the idea that employment of the chick embryo as a useful and informative model system to analyse mammalian gene regulation.
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SARONNI, DAVIDE. « TYROSINE KINASE INHIBITORS IN NEUROENDOCRINE TUMORS : FROM IN VITRO TO ZEBRAFISH MODEL ». Doctoral thesis, Università degli Studi di Milano, 2022. http://hdl.handle.net/2434/917967.
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(1) Background: Neuroendocrine neoplasms (NENs) are a group of tumors that arise from neuroendocrine cells throughout the body, with the lungs and gastrointestinal tract being the most common sites of origin. In patients with NENs and distant metastases, surgery is generally not curative. Although well-differentiated and low-grade NENs, classified as neuroendocrine tumors (NETs), are usually less aggressive than poorly-differentiated NENs, they can develop distant metastases in about 15% of cases. These patients require chronic medical management. However, the clinical efficacy of these treatments is limited by the low objective response rate, due to the occurrence of tumor resistance and the high biological heterogeneity of these neoplasms.
(2) Research problem: We addressed this study on two rare NETs: lung neuroendocrine tumors (LNETs) and medullary thyroid carcinoma (MTC). LNETs represent about 2% of lung tumors, while MTCs are rare thyroid tumors caused by mutations in the RET proto-oncogene. Both NETs are well-differentiated neoplasms and are known to be highly vascularized. Therefore, they represent a potential target for tyrosine kinase inhibitors (TKIs) selective for receptors involved in angiogenesis. The aim of this project was to evaluate the antitumor activity of several new TKIs both in vitro, using LNETs (NCI-H727, UMC-11 and NCI-H835) and MTC (TT and MZ-CRC-1) cell lines, and in vivo, adopting a novel zebrafish xenograft model to study angiogenesis. In LNETs we tested: sulfatinib, a small molecule that inhibits the Vascular Endothelial Growth Factor Receptor (VEGFR) 1, 2, and 3, and the Fibroblast Growth Factor Receptor type 1 (FGFR1); cabozantinib, a multi-target inhibitor selective for VEGFR2, c-Met, Kit, Axl and Flt3; and axitinib, a multi-target TKI of VEGFR1, 2, 3 and Platelet-Derived Growth Factor Receptor-beta (PDGFRβ). In MTC we tested: sulfatinib; SPP86, a RET-specific inhibitor; and SU5402, an inhibitor of the FGFR1 and VEGFR2.
(3) Methodology: In LNETs and MTC cells the effects of selected TKIs have been evaluated in vitro through: MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assays, for assessing cell viability; flow-cytometer analysis, for the evaluation of cell cycle and apoptosis; and wound-healing assay, to study cell migration. In vivo we took advantage of the transgenic zebrafish line of Tg(fli1a:EGFP)y1. Through the xenotransplantation of NET cells in the subperidermal space near the subintestinal vein, we assessed the effects of TKIs on tumor-induced angiogenesis and cancer dissemination.
(4) Key Results: In LNET cell lines we observed a dose-dependent decrease in cell viability after incubation with all TKIs. This effect seems to be related to the perturbation of the cell cycle and induction in apoptosis. In NCI-H727 wound healing assay showed a significant reduction in cell migration only after incubation with cabozantinib. In the zebrafish model, we found a significant reduction of the tumor-induced angiogenesis in implanted LNET cell lines after treatment with all TKIs. Cabozantinib and axitinib were more potent than sulfatinib in inhibition of angiogenesis, while cabozantinib was the most efficient in reducing cell migration from the transplantation site to the tail. In MTC cell lines, sulfatinib, SU5402 and SPP86 showed a decrease in cell viability, confirmed by the significant reduction in S phase cell population. Moreover, sulfatinib and SPP86 showed for both cell lines a significant induction of apoptosis. Sulfatinib and SPP86 inhibited the migration of TT and MZCRC-1 cells, evaluated through the wound healing assay, while SU5402 was able to inhibit migration only in TT cells. In vivo we observed a significant reduction of TT cells-induced angiogenesis in zebrafish embryos after treatment with sulfatinib and SPP86.
(5) Conclusions: Despite sulfatinib resulted the most potent compound in terms of inhibition of LNET cell proliferation, cabozantinib showed in vivo the most effective impact in reducing tumor-induced angiogenesis. Cabozantinib was the only TKI able to inhibit in vivo the dissemination of implanted LNET cells. According to these data, cabozantinib could represent a potential candidate in the therapy of patients with highly vascularized LNET. In MTC cell lines, SPP86 and sulfatinib displayed a similar antitumor activity both in vitro and in vivo, suggesting a good efficacy of specific RET inhibitors (SPP86) with potentially less adverse effects than multitarget TKIs (sulfatinib). In addition, this study showed that the zebrafish model for NETs represents an innovative tool for drug screening with several advantages compared with rodent models: rapidity of procedure, animal immune suppression is not required, lower number of tumor cells for implant and the optical transparency provides a real-time monitoring of cell-stromal interactions and cancer progression in living animals.
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Taylor, Alison Sandra. « Human parthenogenesis : an investigation to determine whether human parthenogentic embryos can be used as an alternative model for embryo research ». Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244020.
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Zhang, Yan. « Implementation of anti-apoptotic peptide aptamers in cell and "in vivo" models of Parkinson's disease ». Thesis, Lyon, École normale supérieure, 2012. http://www.theses.fr/2012ENSL0788.
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La maladie de Parkinson (PD) est considérée comme la deuxième maladie neurodégénérative la plus fréquente. L'examen post-mortem de patients parkinsoniens et des modèles physiologiques d’études de la maladie de Parkinson suggèrent la participation de la mort cellulaire programmée, l'inflammation et l'autophagie dues au stress oxydatif, à des mutations ou l’agrégation de protéines au sein des neurones DA. Les aptamères peptidiques sont de petites protéines combinatoires, consistitués d’une plateforme (dans notre cas, la thiorédoxine humaine, hTRX) et une boucle variable insérée dans le domaine actif de hTRX. Deux aptamères peptidiques ont été identifiés par la sélection fonctionnelle. L’aptamère peptide 32 (Apta-32) ,est spécifique liant deux paralogues T32 impliqués dans le processus d'endocytose. L’aptamère peptidique 34(Apta-34) lie à une cible "T34", une protéine pro-apoptotique ayant un rôle dans la voie apoptotique provenant du noyau. Le travail de cette thèse visait à étudier la fonction anti-apoptotique de nos deux aptamères peptidiques dans deux modèles d’étude de la maladie de Parkinson: un modèle cellulaire (in vitro) et un modèle transgénique D. melanogaster (in vivo). Deux toxines majeures ont été appliquées dans ce travail, 6-hydroxindopamine (6-OHDA) et le paraquat, un pesticide couramment utilisé. Nos observations montrent que la drosophile exprimant Apta-32 dans tous les neurones ont montré une meilleure résistance après 48h de traitement avec le paraquat comparé à deux autre aptamères peptidiques, Apta-34 et Apta-TRX (sans boucle de contrôle variable). Une autre étude a révélé un défaut dans la phagocytose des corps apoptotiques au cours du développement embryonnaire de la drosophile exprimant Apta-32 dans les macrophages, ce qui suggère qu’Apta-32 pourrait participer à et peut-être interférer avec le processus de l’autophygie, et que Apta-32 pourrait protéger contre l'autophagie induite par paraquat dans les neuronesParkinson’s disease is considered as the second most common neurodegenerative disease. Although the cause of the progressive cell loss of PD remains unclear to date, programmed cell death, inflammation and autophagy due to oxidative stress, gene mutations or protein aggregations within DA neuron have been suggested as potential causes. Peptide aptamers are small combinatorial proteins, with a variable loop inserted into a scaffold protein, human thioredoxin, hTRX. They are used to facilitate dissection of signaling networks by modulating specific protein interactions and functions. Two peptide aptamers were identified by functional selection which inhibit Bax-dependent cell death in mammalian models. One peptide aptamer (Apta-32) is binding two paralogues involved in endocytotic trafficking T32. The second peptide aptamer (Apta-34) is binding to a target "T34", a pro-apoptotic protein mediating apoptosis emanating from the nucleus. The work of my PhD thesis aimed to investigate the anti-apoptotic function of our two peptide aptamers in different PD models including cell model (in vitro), brain tissue slice and D. melanogaster (in vivo) ; in particular their impact on neuron survival after exposure to specific toxins. Two major toxins were applied in this work, 6-hydroxindopamine (6-OHDA) and Paraquat, a commonly used pesticide. Our observations indicated that Drosophila expressing Apta-32 in all neurons showed more resistance 48h after treatment with Paraquat, compared to drosophila expressing Apta-34 or TRX. Another study revealed a defect in phagocytosis of apoptotic bodies in drosophila embryo’s expressing Apta-32 in macrophage, suggesting Apta-32 could be involved in, and perhaps interfere with, the process of autophagy. This suggests that Apta-32 could protect against paraquat induced autophagy in neurons
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Reimers, Mark J. « Ethanol-dependent developmental toxicity in zebrafish / ». Connect to full text via ProQuest. IP filtered, 2005.
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Bikow, Jennifer. « Establishment of Zebrafish Models for Studying Mesenchymal Stromal Cell Therapy for Cardiac Disease ». Thesis, 2010. http://hdl.handle.net/1807/25433.
Texte intégralRésumé :
Bone marrow (BM)-derived mesenchymal stromal cells (MSCs) can be induced to express cardiac-specific markers by embryonic cardiomyocytes in vitro. To determine whether this phenomenon occurs in vivo, we have developed a cell transplantation system using zebrafish embryonic recipients. We were unable to isolate expandable zebrafish kidney stromal (ZKS) cells from the kidney, the human BM equivalent; hence, we analyzed the established ZKS1 cell line. We found that ZKS1 expresses stromal genes, but also expresses hematopoietic genes not normally expressed by MSCs. Furthermore, we were unable to differentiate ZKS1 cells into adipocytes, osteoblasts or cardiomyocytes in vitro. We created a transgenic ZKS1(CMV:eGFP) cell line which, after transplantation into zebrafish blastulae, was observed within the host heart, among other tissues. Finally, pT2/S2tnnt2-GM2 and pT2/S2tnnt2-DsRed transposons were generated to mark ZKS1 cardiac differentiation. The zebrafish model established here will be useful for studying the molecular mechanisms of exogenous MSC cardiac differentiation in vivo.
Livres sur le sujet "Embryo, Disease Model"
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The influence of ethyl alcohol on the development of the chondrocranium of Gallus gallus. Berlin : Springer, 1996.
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Benedito, Rui, et Arndt F. Siekmann. Blood vessel differentiation and growth. Sous la direction de José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso et Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0016.
Texte intégralRésumé :
A variety of diseases are related to or dependent on the vascular system. Several lines of evidence show that adequate manipulation of the vascular function in disease requires targeting and interfering with the same molecular pathways and cellular processes that act to form vessels during embryo or organ development. Therefore an understanding of the mechanisms that regulate vascular development in this non-pathological context is of major importance, since it may lead to better ways of treating vascular-related pathologies. This chapter covers the most significant cellular and molecular mechanisms involved in the origin, life, and death of the endothelial cellwhich is involved in several important developmental and pathological processes. Most of the mechanisms described were identified in animal model systems. However, owing to the high evolutionary conservation of these, they are likely be very similar to those occurring in humans and in disease.
Chapitres de livres sur le sujet "Embryo, Disease Model"
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Fischer, Bernd, Maria Schindler, S. Mareike Pendzialek, Jacqueline Gürke, Elisa Haucke, Katarzyna Joanna Grybel, René Thieme et Anne Navarrete Santos. « The Long-Term Effect of the Periconception Period on the Embryo’s Epigenetic Profile and Phenotype : The Role of Maternal Disease Such as Diabetes and How the Effect Is Mediated (Example from a Rabbit Model) ». Dans Periconception in Physiology and Medicine, 107–15. Cham : Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-62414-3_6.
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Ludlow, Karinne. « MRT in Australia ». Dans Reproduction Reborn, 108—C5P78. Oxford University PressNew York, 2023. http://dx.doi.org/10.1093/oso/9780197616192.003.0006.
Texte intégralRésumé :
Abstract In 2021, the Australian federal government introduced draft legislation that, when enacted, made Australia the second international jurisdiction to expressly legalise clinical mitochondrial replacement therapies (MRT). These changes provide a model for other countries, including attempts to future-proof, rejection of limiting use to male embryos, and identification of mitochondrial DNA donors. The changes needed to address Australia’s out-of-date and splintered regulatory framework around human embryos, including prohibitions on embryos containing genetic material of more than two people. Advocacy by mitochondrial disease community groups, following scientific developments and United Kingdom’s legalisation of clinical MRT, have driven a government traditionally reluctant to engage with issues of embryo research to act. This chapter considers the existing Australian regulatory framework around MRT and what led to its construction before explaining what led to moves to allow clinical MRT. After describing the recent reforms, what this means for the future of MRT and heritable genome editing is then discussed.
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Cui, Chao, Erica L. Benard, Zakia Kanwal, Oliver W. Stockhammer, Michiel van der Vaart, Anna Zakrzewska, Herman P. Spaink et Annemarie H. Meijer. « Infectious Disease Modeling and Innate Immune Function in Zebrafish Embryos ». Dans The Zebrafish : Disease Models and Chemical Screens, 273–308. Elsevier, 2011. http://dx.doi.org/10.1016/b978-0-12-381320-6.00012-6.
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Bale, Tracy L. « Epigenetics in Early Life Programming ». Dans Neurobiology of Mental Illness, sous la direction de Joseph D. Buxbaum, 955–66. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199934959.003.0072.
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Fetal antecedents such as maternal stress, infection or dietary challenges have long been associated with an increased disease risk, capable of affecting multiple generations. The mechanisms through which such determinants contribute to disease development likely involve complex and dynamic relationships between the maternal environment, the endocrine placenta, and the epigenetic programming of the developing embryo itself. While an appreciation for the importance of the epigenome in offspring disease predisposition had evolved, the incredible variability in critical factors such as gestational timing of insults, sex of the fetus, and maternal genetics make clear interpretations difficult. However, animal models have proven highly informative in providing the best knowledge yet as to just how dynamically responsive the epigenome is, and in determining important mechanisms that shape and reprogram the developing brain. This chapter will discuss the epidemiological and clinical evidence and supportive animal models related to environmental influences on neurodevelopmental and neuropsychiatric disease risk.
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Parrington, John. « Next Year’s Models ». Dans Redesigning Life, 111–32. Oxford University Press, 2020. http://dx.doi.org/10.1093/oso/9780198766834.003.0006.
Texte intégralRésumé :
Animal ‘models’ of health and disease have been central to biomedical science since at least when William Harvey used dogs to illustrate the fact that blood is pumped by the heart through the arteries and then through the veins back to the heart. In the 1980s, a major step forward came with the discovery of embryonic stem cells and ways to manipulate these genetically and then inject into mouse embryos, resulting in the creation of knockout and knockin mice with deletions, or more subtle changes, in specific genes. Unfortunately, it has been impossible to isolate embryonic stem cells from any other species besides mice, and more recently rats and humans. Yet rodents are far from the best animals for modelling, say the body’s metabolism or heart function and disease, or brain function and mental disorders. Instead, pigs and primates are potentially far better models for these respective areas of research. CRISPR/Cas genome editing has made it possible for the first time to create precisely genome edited versions of pigs, monkeys, and any other species that may provide a better model of specific aspects of human health and disease, than rodents. So genetically modified pigs might be used to study heart disease, but also provide hearts for human transplantation, while GM monkeys might help us better understand the biological basis of mental disorders such as depression or schizophrenia. However, this area of research is raising ethical issues about the creation of monkeys with human versions of particular genes, and how this might affect their behaviour and personality.
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Wyllie, Andrew H., et Mark J. Arends. « Apoptosis in health and disease ». Dans Oxford Textbook of Medicine, 177–88. Oxford University Press, 2010. http://dx.doi.org/10.1093/med/9780199204854.003.0406.
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Apoptosis is the process by which single cells die in the midst of living tissues. It is responsible for most—perhaps all—of the cell-death events that occur during the formation of the early embryo and the sculpting and moulding of organs. Apoptotic cell death continues to play a critical role in the maintenance of cell numbers in those tissues in which cell turnover persists into adult life, such as the epithelium of the gastrointestinal tract, the bone marrow, and lymphoid system including both B- and T-cell lineages. Apoptosis is the usual mode of death in the targets of natural killer (NK) cells and cytotoxic T-cells, and in involution and atrophy induced by hormonal and other stimuli. It also appears in the reaction of many tissues to injury, including mild degrees of ischaemia, exposure to ionizing and ultraviolet radiation, or treatment with cancer chemotherapeutic drugs. Excessive or too little apoptosis play a significant part in the pathogenesis of autoimmunity, infectious disease, AIDS, stroke, myocardial disease, and cancer. When cancers regress, apoptosis is part of the mechanism involved. Here the cellular processes and molecular mechanisms of apoptosis are set out, together with a conspectus of its involvement in many diseases....
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Sato, Masahiro, Masato Ohtsuka, Emi Inada, Shingo Nakamura, Issei Saitoh et Shuji Takabayashi. « Recent Advances in In Vivo Genome Editing Targeting Mammalian Preimplantation Embryos ». Dans CRISPR Technology [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106873.
Texte intégralRésumé :
CRISPR-based genome engineering has been widely used for producing gene-modified animals such as mice and rats, to explore the function of a gene of interest and to create disease models. However, it always requires the ex vivo handling of preimplantation embryos, as exemplified by the microinjection of genome editing components into zygotes or in vitro electroporation of zygotes in the presence of genome editing components, and subsequent cultivation of the treated embryos prior to egg transfer to the recipient females. To avoid this ex vivo process, we have developed a novel method called genome-editing via oviductal nucleic acids delivery (GONAD) or improved GONAD (i-GONAD), which enables in situ genome editing of zygotes present in the oviductal lumen of a pregnant female. This technology does not require any ex vivo handling of preimplantation embryos or preparation of recipient females and vasectomized males, all of which are often laborious and time-consuming. In this chapter, recent advances in the development of GONAD/i-GONAD will be described.
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Pérez-Pomares, José M., et José L. de la Pompa. « Development of the ventricles and valves ». Dans ESC CardioMed, sous la direction de Miguel Torres, 44–49. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0007.
Texte intégralRésumé :
The heart is the first functional organ of the vertebrate embryo, beginning to beat at around 4 weeks of gestation in humans. Tissue interactions orchestrate the complex patterning, proliferation, and differentiation processes that transform the embryonic cardiac primordium into the adult heart. During heart embryogenesis, cardiac mesoderm progenitor cells originate bilaterally during gastrulation and move rostrally to form the primitive heart tube, which will then loop towards the right and initiate septation to give rise to the mature four-chambered heart. Experimental studies in animal models have revealed the crucial role that a number of highly conserved signalling pathways, involving active molecular cross-talk between adjacent tissues, play in cardiac development, and how the alterations in these signalling mechanisms may cause congenital heart disease affecting the neonate or adult. Here, we describe briefly the knowledge gained on the molecular and cellular mechanisms underlying cardiac chamber and valve development and its implication in disease. This knowledge will ultimately facilitate the design of diagnostic and therapeutic strategies to treat congenital heart disease.
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Pérez-Pomares, José M., et José L. de la Pompa. « Development of the ventricles and valves ». Dans ESC CardioMed, sous la direction de Miguel Torres, 44–49. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0007_update_001.
Texte intégralRésumé :
The heart is the first functional organ of the vertebrate embryo, beginning to beat at around 4 weeks of gestation in humans. Tissue interactions orchestrate the complex patterning, proliferation, and differentiation processes that transform the embryonic cardiac primordium into the adult heart. During heart embryogenesis, cardiac mesoderm progenitor cells originate bilaterally during gastrulation and move rostrally to form the primitive heart tube, which will then loop towards the right and initiate septation to give rise to the mature four-chambered heart. Experimental studies in animal models have revealed the crucial role that a number of highly conserved signalling pathways, involving active molecular cross-talk between adjacent tissues, play in cardiac development, and how the alterations in these signalling mechanisms may cause congenital heart disease affecting the neonate or adult. Here, we describe briefly the knowledge gained on the molecular and cellular mechanisms underlying cardiac chamber and valve development and its implication in disease. This knowledge will ultimately facilitate the design of diagnostic and therapeutic strategies to treat congenital heart disease.
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Pérez-Pomares, José M., et José L. de la Pompa. « Development of the ventricles and valves ». Dans ESC CardioMed, sous la direction de Miguel Torres, 44–49. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0007_update_002.
Texte intégralRésumé :
The heart is the first functional organ of the vertebrate embryo, beginning to beat at around 4 weeks of gestation in humans. Tissue interactions orchestrate the complex patterning, proliferation, and differentiation processes that transform the embryonic cardiac primordium into the adult heart. During heart embryogenesis, cardiac mesoderm progenitor cells originate bilaterally during gastrulation and move rostrally to form the primitive heart tube, which will then loop towards the right and initiate septation to give rise to the mature four-chambered heart. Experimental studies in animal models have revealed the crucial role that a number of highly conserved signalling pathways, involving active molecular cross-talk between adjacent tissues, play in cardiac development, and how the alterations in these signalling mechanisms may cause congenital heart disease affecting the neonate or adult. Here, we describe briefly the knowledge gained on the molecular and cellular mechanisms underlying cardiac chamber and valve development and its implication in disease. This knowledge will ultimately facilitate the design of diagnostic and therapeutic strategies to treat congenital heart disease.
Actes de conférences sur le sujet "Embryo, Disease Model"
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Abbasi, Ali A., M. T. Ahmadian, Ali Alizadeh et S. Tarighi. « Application of Hyperelastic Models in Mechanical Properties Prediction of Mouse Oocyte and Embryo Cells at Large Deformations ». Dans ASME 2016 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2016. http://dx.doi.org/10.1115/imece2016-65034.
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Biological cell studies have many applications in biology, cell manipulation and diagnosis of diseases such as cancer and malaria. In this study, inverse finite element method (IFEM) combined with Levenberg-Marquardt optimization algorithm has been used to extract and characterize material properties of mouse oocyte and embryo cells at large deformations. Then, the simulation results have been validated using data from experimental works. In this study, it is assumed cell material is hyperelastic, isotropic, homogenous and axisymmetric. For inverse analysis, FEM model of cell injection experiment which implemented in Abaqus software has been coupled with Levenberg-Marquardt optimization algorithm written in Matlab; based on this coupling the optimum hyperelastic coefficients which give the best match between experimental and simulated forces are extracted. Results show that among different hyperelastic material models, Ogden material is well suitable for characterization of mouse oocyte cell and Mooney-Rivlin or polynomial are suitable for characterization of mouse embryo cell. Moreover the evaluated Poisson ratio of the cell is obtained to be equal to 0.5, which indicates the structural material of mouse oocyte and embryo, are compressible.
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Moussa, Heba Adel Mohamed Lotfy, Gawaher Saleh Abbas Mahgoub, Mashael Ali H. I. Al-Badr et Huseyin Cagatay Yalcin. « Investigating the Cardiac Effects of Sildenafil loaded Nanoparticles on Heart Failure using the Zebrafish Embryo Model ». Dans Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2020. http://dx.doi.org/10.29117/quarfe.2020.0217.
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Background: Cardiovascular diseases (CVDs) are the first cause of death worldwide. Vasolidator agents are used to relax cardiac muscle, but their extremely short half-lifes limit their effectiveness. Sildenafil is such an agent used to relax the blood vessels muscles and increase the blood flow. The conventional drug can lead to serious problems in patients duo to the systematic drug delivery. Use of Nanomedicine potentially can enhance delivery of this agent while reducing the systematic effect of the drug. Aim: The purpose of the research is to examine the effectiveness sildenafil loaded nanoparticles in rescuing heart failure using zebrafish embryo model. Methods: There will be five experimental groups. The zebrafish will be treated with Aristolochic Acid (AA) at 24 hour per fertilization (hpf) to create the heart injury group. The treatment groups will be heart injury followed by a dose of either Sildenafil or Sildenafil loaded nanoparticles at 36 hpf. Two control groups will be the negative control (exposed to egg water) and vehicle control (exposed to the Dimethylsulfoxide (DMSO)).To evaluate the drug effects on embryo, toxicity assessment (Survival rate, tail flicking and hatching rate), cardiotoxicity assessment and gene expression of heart injury marker via RT-PCR will be conducted. Results: Preliminary findings demonstrate, loading Sildenafil to nanoparticles enhances its effectiveness dramatically. The experiments are ongoing to confirm the results. Conclusion: Nanomedicine is a powerful approach to enhance cardiovascular therapy. Vasodilator drugs in particular will benefit from this improvement as demonstrated with our findings
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Al-Ansari, Dana E., Nura A. Mohamed, Isra Marei, Huseyin Yalcin et Haissam Abou-Saleh. « Assessment of Metal Organic Framework as Potential Drug Carriers in Cardiovascular Diseases ». Dans Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2020. http://dx.doi.org/10.29117/quarfe.2020.0127.
Texte intégralRésumé :
Background: Cardiovascular diseases (CVDs) are considered the major cause of death worldwide. Therapeutic delivery to the cardiovascular system may play an important role in the successful treatment of a variety of CVDs, including atherosclerosis, ischemic-reperfusion injury, and microvascular diseases. Despite their clinical benefits, current therapeutic drugs are hindered by their short half-life and systemic side effects. This limitation could be overcome using controlled drug release with the potential for targeted drug delivery using a nanomedicine approach. In the current study, we have assessed the use of a highly porous nano-sized preparation of iron-based Metal-organic Framework (MOF) commonly referred to as MIL-89 as potential drug carriers in the cardiovascular system. Aims: To assess the effect of MOFs on the viability and cytotoxicity of human vascular cells and the cellular uptake in vitro, and the organ-system toxicity of MOF in vivo using the Zebrafish model. Methods: Human pulmonary endothelial cells (HPAECs) and pulmonary smooth muscle cells (HPASMCs) were treated with variable concentrations of MOFs. The viability, cytotoxicity and anti-inflammatory effects were measured using AlamarBlue, LDH assay and ELISA. The cellular uptake of MOFs were assessed using light, confocal, and transmission electron microscopes and EDS analysis. Moreover, Zebrafish embryos were cultured and treated with MOFs-nanoparticles at 0 hours post fertilization (hpf) followed by different organ-specific assays at 24, 48, and 72 hpf. Results: Although MOFs affect the viability at high concentrations, it does not cause any significant cytotoxicity on HPAECs and HPASMCs. Interestingly, MOFs were shown to have an anti-inflammatory effect. Microscopic images showed an increased (concentration-dependent) cellular uptake of MOFs and transfer to daughter cells in both cell types. Moreover, the in vivo study showed that high concentrations of MOFs delay zebrafish embryos hatching and cause heart deformation, which is currently investigated using cardiotoxicity markers. Conclusion: MOFs is a promising nanoparticle prototypes for drug delivery in the cardiovascular system with high cellular uptake and anti-inflammatory effects. Further investigations of MOFs, including diseased models and drug- loaded formulation is required.
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García Vázquez, Milagros. « La pedagogía de la Bauhaus como modelo para la expresión plural en las comunidades artísticas actuales ». Dans IV Congreso Internacional Estética y Política : Poéticas del desacuerdo para una democracia plural. València : Editorial Universitat Politècnica de València, 2019. http://dx.doi.org/10.4995/cep4.2019.10317.
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En 1933, un gobierno totalitario cerraba las puertas de una de las comunidades artísticas más significativas para la Historia del Arte del siglo XX y del actual, tanto desde el punto de vista de la creación, como de la pedagogía de las artes: la Bauhaus. Aquella clausura no supuso, sin embargo, su fin. En 1937 tomaría su testigo la New Bauhaus, abierta en Chicago por László Moholy-Nagy, uno de los profesores más influyentes en la plantilla de aquella institución creada por Walter Gropius en 1919. Su nombre ha variado desde entonces, «Chicago School of Design» (1939), «Institute of Design» (1944), hasta llegar a integrarse en el «Illinois Institute of Technology», existente en la actualidad. El paréntesis entre dos guerras mundiales había sido ocasión para el encuentro de artistas, especialistas en diversos ámbitos de la creación y de diferentes orígenes culturales, con un objetivo común, formar a otros creadores para «desear, proyectar y crear todos juntos la nueva estructura del futuro», como decía Gropius en el manifiesto original. Su pretendido final, impuesto por un régimen político, encontró su punto y aparte en un estado democrático al otro lado del Atlántico, dando pie no solo a una iniciativa mantenida a nivel académico en el Instituto de Illinois, sino inspirando a otra, fuera de las estructuras estatales, que puede servir a su vez como ejemplo de aplicación creativa del presente disenso en las culturas democráticas. Precisamente en Chicago surgiría, en 1990, un proyecto de la mano de la Fundación MacArthur, para potenciar la diversidad artística y cultural y orientarla hacia una meta, reconocer y promover procesos creativos y nuevas ideas como cauces esenciales en la mejora de la vida. Se dotaría económicamente a una serie de instituciones artísticas, colonias, comunidades o residencias de artistas, para celebrar un encuentro llamado «Special Initiative on Artists». De aquella reunión que tuvo lugar en 1991, surgió la creación de un consorcio internacional de comunidades artísticas, hoy conocida como «Alliance of Artists Communities», donde la formación y la puesta en común de trabajos y nuevos proyectos son los ejes fundamentales. Quizá pueda ser este un ejemplo de salto creativo por encima de las barreras de las políticas del consenso, si fracasan, o del desacuerdo, si tienen lugar.