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1
Morant, Laura, Maria-Luise Petrovic-Erfurth, and Albena Jordanova. "An Adapted GeneSwitch Toolkit for Comparable Cellular and Animal Models: A Proof of Concept in Modeling Charcot-Marie-Tooth Neuropathy." International Journal of Molecular Sciences 24, no. 22 (November 9, 2023): 16138. http://dx.doi.org/10.3390/ijms242216138.
Abstract:
Investigating the impact of disease-causing mutations, their affected pathways, and/or potential therapeutic strategies using disease modeling often requires the generation of different in vivo and in cellulo models. To date, several approaches have been established to induce transgene expression in a controlled manner in different model systems. Several rounds of subcloning are, however, required, depending on the model organism used, thus bringing labor-intensive experiments into the technical approach and analysis comparison. The GeneSwitch™ technology is an adapted version of the classical UAS-GAL4 inducible system, allowing the spatial and temporal modulation of transgene expression. It consists of three components: a plasmid encoding for the chimeric regulatory pSwitch protein, Mifepristone as an inducer, and an inducible plasmid. While the pSwitch-containing first plasmid can be used both in vivo and in cellulo, the inducible second plasmid can only be used in cellulo. This requires a specific subcloning strategy of the inducible plasmid tailored to the model organism used. To avoid this step and unify gene expression in the transgenic models generated, we replaced the backbone vector with standard pUAS-attB plasmid for both plasmids containing either the chimeric GeneSwitch™ cDNA sequence or the transgene cDNA sequence. We optimized this adapted system to regulate transgene expression in several mammalian cell lines. Moreover, we took advantage of this new system to generate unified cellular and fruit fly models for YARS1-induced Charco–Marie–Tooth neuropathy (CMT). These new models displayed the expected CMT-like phenotypes. In the N2a neuroblastoma cells expressing YARS1 transgenes, we observed the typical “teardrop” distribution of the synthetase that was perturbed when expressing the YARS1CMT mutation. In flies, the ubiquitous expression of YARS1CMT induced dose-dependent developmental lethality and pan-neuronal expression caused locomotor deficit, while expression of the wild-type allele was harmless. Our proof-of-concept disease modeling studies support the efficacy of the adapted transgenesis system as a powerful tool allowing the design of studies with optimal data comparability.
2
Dasnur Nanjappa, Madhusudan, Anup Pandith, Svetlana Sankaran, Dorothy Priyanka Dorairaj, Anusha Anjaneya Reddy, and Hari Prasad Badubanahalli Ramesh. "Recent Advancements in Developments of Novel Fluorescent Probes: In Cellulo Recognitions of Alkaline Phosphatases." Symmetry 14, no. 8 (August 9, 2022): 1634. http://dx.doi.org/10.3390/sym14081634.
Abstract:
Alkaline phosphatase (ALP) is one of the vital phospho-ester bond cleaving biocatalysts that has inevitable significance in cellular systems, viz., early-stage osteoblast differentiation, cell integrity in tissues, bone mineralization, cancer biomarker, liver dysfunction, cellular osmotic pressure, protein folding and many more. Variation from optimal levels of ALP in intra and extracellular fluids can cause severe diseases, including death. Due to these reasons, ALP is considered as a vital biomarker for various preclinical and medical diagnosis. Fluorescence image-based diagnosis is the most widely used method, owing to its simplicity, robustness, non-invasive properties and excellent spatio-temporal resolution (up to the nM/pM level), as compared to conventional analytical techniques, such as the electroanalytical method, nuclear magnetic resonance (NMR) and high-performance liquid chromatography (HPLC). Most of the reviews reported for ALP’s recognition in the literature scarcely explain the structurally related, photophysical and biophysical parameters; and the sub-cellular localizations. Considering these facts, in order to enhance the opto-analytical parameters of fluorescence-based diagnostic materials at the cellular level, herein we have systematically documented recent developments in the opto-analytical capabilities of quencher-free probes for ALP, used in in vitro (biological buffers) to in cellulo conditions, along with in vivo models.
3
Sailer, Alexander, Franziska Ermer, Yvonne Kraus, Rebekkah Bingham, Ferdinand H. Lutter, Julia Ahlfeld, and Oliver Thorn-Seshold. "Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo." Beilstein Journal of Organic Chemistry 16 (January 27, 2020): 125–34. http://dx.doi.org/10.3762/bjoc.16.14.
Abstract:
Background: Hemithioindigo is a promising molecular photoswitch that has only recently been applied as a photoswitchable pharmacophore for control over bioactivity in cellulo. Uniquely, in contrast to other photoswitches that have been applied to biology, the pseudosymmetric hemithioindigo scaffold has allowed the creation of both dark-active and lit-active photopharmaceuticals for the same binding site by a priori design. However, the potency of previous hemithioindigo photopharmaceuticals has not been optimal for their translation to other biological models. Results: Inspired by the structure of tubulin-inhibiting indanones, we created hemithioindigo-based indanone-like tubulin inhibitors (HITubs) and optimised their cellular potency as antimitotic photopharmaceuticals. These HITubs feature reliable and robust visible-light photoswitching and high fatigue resistance. The use of the hemithioindigo scaffold also permitted us to employ a para-hydroxyhemistilbene motif, a structural feature which is denied to most azobenzenes due to the negligibly short lifetimes of their metastable Z-isomers, which proved crucial to enhancing the potency and photoswitchability. The HITubs were ten times more potent than previously reported hemithioindigo photopharmaceutical antimitotics in a series of cell-free and cellular assays, and allowed robust photocontrol over tubulin polymerisation, microtubule (MT) network structure, cell cycle, and cell survival. Conclusions: HITubs represent a powerful addition to the growing toolbox of photopharmaceutical reagents for MT cytoskeleton research. Additionally, as the hemithioindigo scaffold allows photoswitchable bioactivity for substituent patterns inaccessible to the majority of current photopharmaceuticals, wider adoption of the hemithioindigo scaffold may significantly expand the scope of cellular and in vivo targets addressable by photopharmacology.
4
Thompson, John W., Omar Elwardany, David J. McCarthy, Dallas L. Sheinberg, Carlos M. Alvarez, Ahmed Nada, Brian M. Snelling, Stephanie H. Chen, Samir Sur, and Robert M. Starke. "In vivo cerebral aneurysm models." Neurosurgical Focus 47, no. 1 (July 2019): E20. http://dx.doi.org/10.3171/2019.4.focus19219.
Abstract:
Cerebral aneurysm rupture is a devastating event resulting in subarachnoid hemorrhage and is associated with significant morbidity and death. Up to 50% of individuals do not survive aneurysm rupture, with the majority of survivors suffering some degree of neurological deficit. Therefore, prior to aneurysm rupture, a large number of diagnosed patients are treated either microsurgically via clipping or endovascularly to prevent aneurysm filling. With the advancement of endovascular surgical techniques and devices, endovascular treatment of cerebral aneurysms is becoming the first-line therapy at many hospitals. Despite this fact, a large number of endovascularly treated patients will have aneurysm recanalization and progression and will require retreatment. The lack of approved pharmacological interventions for cerebral aneurysms and the need for retreatment have led to a growing interest in understanding the molecular, cellular, and physiological determinants of cerebral aneurysm pathogenesis, maturation, and rupture. To this end, the use of animal cerebral aneurysm models has contributed significantly to our current understanding of cerebral aneurysm biology and to the development of and training in endovascular devices. This review summarizes the small and large animal models of cerebral aneurysm that are being used to explore the pathophysiology of cerebral aneurysms, as well as the development of novel endovascular devices for aneurysm treatment.
5
Lepore Signorile, Martina, Valentina Grossi, Candida Fasano, Giovanna Forte, Vittoria Disciglio, Paola Sanese, Katia De Marco, et al. "c-MYC Protein Stability Is Sustained by MAPKs in Colorectal Cancer." Cancers 14, no. 19 (October 4, 2022): 4840. http://dx.doi.org/10.3390/cancers14194840.
Abstract:
c-MYC is one of the most important factors involved in colorectal cancer (CRC) initiation and progression; indeed, it is found to be upregulated in up to 80% of sporadic cases. During colorectal carcinogenesis, c-MYC is maintained upregulated through β-catenin-mediated transcriptional activation and ERK-mediated post-translational stabilization. Our data demonstrate that p38α, a kinase involved in CRC metabolism and survival, contributes to c-Myc protein stability. Moreover, we show that p38α, like ERK, stabilizes c-MYC protein levels by preventing its ubiquitination. Of note, we found that p38α phosphorylates c-MYC and interacts with it both in vitro and in cellulo. Extensive molecular analyses in the cellular and in vivo models revealed that the p38α kinase inhibitors, SB202190 and ralimetinib, affect c-MYC protein levels. Ralimetinib also exhibited a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Overall, our findings identify p38α as a promising therapeutic target, acting directly on c-MYC, with potential implications for countering c-MYC-mediated CRC proliferation, metastatic dissemination, and chemoresistance.
6
Mode, Selma, Maren Ketterer, Maxime Québatte, and Christoph Dehio. "Antibiotic persistence of intracellular Brucella abortus." PLOS Neglected Tropical Diseases 16, no. 7 (July 26, 2022): e0010635. http://dx.doi.org/10.1371/journal.pntd.0010635.
Abstract:
Background Human Brucellosis caused by the facultative intracellular pathogen Brucella spp. is an endemic bacterial zoonosis manifesting as acute or chronic infections with high morbidity. Treatment typically involves a combination therapy of two antibiotics for several weeks to month, but despite this harsh treatment relapses occur at a rate of 5–15%. Although poor compliance and reinfection may account for a fraction of the observed relapse cases, it is apparent that the properties of the infectious agent itself may play a decisive role in this phenomenon. Methodology/Principal findings We used B. abortus carrying a dual reporter in a macrophage infection model to gain a better understanding of the efficacy of recommended therapies in cellulo. For this we used automated fluorescent microscopy as a prime read-out and developed specific CellProfiler pipelines to score infected macrophages at the population and the single cell level. Combining microscopy of constitutive and induced reporters with classical CFU determination, we quantified the protective nature of the Brucella intracellular lifestyle to various antibiotics and the ability of B. abortus to persist in cellulo despite harsh antibiotic treatments. Conclusion/Significance We demonstrate that treatment of infected macrophages with antibiotics at recommended concentrations fails to fully prevent growth and persistence of B. abortus in cellulo, which may be explained by a protective nature of the intracellular niche(s). Moreover, we show the presence of bona fide intracellular persisters upon antibiotic treatment, which are metabolically active and retain the full infectious potential, therefore constituting a plausible reservoir for reinfection and relapse. In conclusion, our results highlight the need to extend the spectrum of models to test new antimicrobial therapies for Brucellosis to better reflect the in vivo infection environment, and to develop therapeutic approaches targeting the persister subpopulation.
7
Qiu, Xudong, Seth T. Gammon, James R. Johnson, Federica Pisaneschi, Steven W. Millward, Edward M. Barnett, and David Piwnica-Worms. "Apoptosis Detection in Retinal Ganglion Cells Using Quantitative Changes in Multichannel Fluorescence Colocalization." Biosensors 12, no. 9 (August 28, 2022): 693. http://dx.doi.org/10.3390/bios12090693.
Abstract:
KcapTR488 is a dual-fluorophore peptide sensor for the real-time reporting of programmed cell death by fluorescence imaging. KcapTR488 contains a nuclear localization sequence (NLS) conjugated with Texas Red, a caspase-cleavable sequence (DEVD), and a C-terminus conjugated to Alexa Fluor 488 (AF488). The synthesis and preliminary evaluation in cellulo of KcapTR488 for monitoring cell death by fluorescence imaging has been previously reported, but its utility in vivo has yet to be tested or validated. Herein, in vitro solution experiments verified the intramolecular fluorescence resonance energy transfer (FRET) between the two fluorophores and enabled a quantitative analysis of enzyme rates and selectivity. The sensor delivery kinetics in live rat models were quantified by ex vivo fluorescence microscopy. Studies in healthy control retinas demonstrated that KcapTR488 concentrated in the nucleus of retinal ganglion cells (RGC), with a strong colocalization of red and green fluorescence signals producing robust FRET signals, indicating an intact reporter. By contrast, using an acute but mild NMDA-induced retinal injury model, dual-color confocal ex vivo microscopy of cleaved KcapTR488 identified sensor activation as early as 2 h after injection. Quantitative changes in fluorescence colocalization were superior to changes in FRET for monitoring injury progression. Longitudinal monitoring revealed that the NLS-Texas Red fragment of the cleaved sensor moved out of the cell body, down the axon, and exited the retina, consistent with anterograde axonal transport. Thus, KcapTR488 may be a powerful tool to study RGC death pathways in live preclinical models of glaucoma.
8
Reinhardt, Christoph, and Heiko Rühl. "Animal and Cellular Models in Thrombosis and Hemostasis." Hämostaseologie 43, no. 05 (October 2023): 319–20. http://dx.doi.org/10.1055/a-2031-7975.
Abstract:
Abstract Standardized In Vitro and In Vivo Model Systems to Simplify Complexity—That's How We Learn The discovery of new target molecules and translational progress in the development and refinement of antithrombotic therapies as well as the improved treatment of bleeding disorders strongly relies on standardized ex vivo and in vivo models that closely resemble the respective human pathologies. The standardization of these models requires sound training in specialized hemostasis and thrombosis research laboratories as well as a consistent daily routine. In this theme issue of Hämostaseologie—Progress in Haemostasis, four review articles cover key models that have proven instrumental to gain mechanistic insights on thrombogenesis and hemostatic processes. In recent decades, these models have moved our field forward and enabled translation across scales, from cell-based research to isolated flow chamber systems, to mouse thrombosis models reflecting the pathologic situations as observed in patients, to large animal models.
9
Irrera, Pietro, Miriam Roberto, Lorena Consolino, Annasofia Anemone, Daisy Villano, Victor Navarro-Tableros, Antonella Carella, Walter Dastrù, Silvio Aime, and Dario Livio Longo. "Effect of Esomeprazole Treatment on Extracellular Tumor pH in a Preclinical Model of Prostate Cancer by MRI-CEST Tumor pH Imaging." Metabolites 13, no. 1 (December 28, 2022): 48. http://dx.doi.org/10.3390/metabo13010048.
Abstract:
Novel anticancer treatments target the pH regulating system that plays a major role in tumor progression by creating an acidic microenvironment, although few studies have addressed their effect on tumor acidosis. In this study, we investigated in vivo several proton pump inhibitors (PPIs) targeting NHE-1 (Amiloride and Cariporide) and V-ATPase (Esomeprazole and Lansoprazole) proton transporters in the DU145 androgen-insensitive human prostate cancer model. In cellulo results showed that DU145 are sensitive, with decreasing efficacy, to Amiloride, Esomeprazole and Lansoprazole, with marked cell toxicity both in normoxia and in hypoxia, with almost any change in pH. In vivo studies were performed upon administration of Esomeprazole to assess both the acute and chronic effects, and Iopamidol-based tumor pH imaging was performed to evaluate tumor acidosis. Although statistically significant tumor pH changes were observed a few hours after Esomeprazole administration in both the acute study and up to one week of treatment in the chronic study, longer treatment resulted in a lack of changes in tumor acidosis, which was associated to similar tumor growth curves between treated and control groups in both the subcutaneous and orthotopic models. Overall, this study highlights MRI-CEST tumor pH imaging as a valid approach to monitoring treatment response to PPIs.
10
Kuhn, Deborah J., Qing Chen, Peter M. Voorhees, John S. Strader, Kevin D. Shenk, Congcong M. Sun, Susan D. Demo, Mark K. Bennett, Fred W. van Leeuwen, and Robert Z. Orlowski. "The Novel, Irreversible Proteasome Inhibitor PR-171 Demonstrates Potent Anti-Tumor Activity in Pre-Clinical Models of Multiple Myeloma, and Overcomes Bortezomib Resistance." Blood 108, no. 11 (November 16, 2006): 3461. http://dx.doi.org/10.1182/blood.v108.11.3461.3461.
Abstract:
Abstract Introduction: The ubiquitin-proteasome pathway has been validated as a therapeutic target with the approval of the small molecule proteasome inhibitor, bortezomib (VELCADE®), in multiple myeloma and non-Hodgkin lymphoma. However, the overall response rate of patients with multiple myeloma in phase III clinical trials was 43%, underscoring the need for a next generation of inhibitors with the potential for greater efficacy. Methods: PR-171 is a novel, tetrapeptide epoxomicin-related inhibitor that binds the proteasome irreversibly, and our objectives were to evaluate its activity and mechanism of action in pre-clinical models of multiple myeloma. Results: PR-171 potently bound and inhibited the chymotrypsin-like subunit of the proteasome in vitro, in cellulo, and in vivo at low concentrations. At higher concentrations, however, unlike bortezomib, which targeted the chymotrypsin-like and peptidyl-glutamyl peptide hydrolyzing activities in vivo, PR-171 also displayed significant inhibition of the trypsin-like and the peptidyl-glutamyl peptide hydrolyzing activities. PR-171-induced proteasome inhibition was associated with accumulation of polyubiquitinated substrates and pro-apoptotic Bax. Brief pulse PR-171 exposure, which simulates the in vivo pharmacokinetics of bortezomib, led to PR-171-mediated inhibition of cellular proliferation linked to induction of caspase-3-dependent apoptosis through both intrinsic (caspase-9) and extrinsic (caspase-8-dependent) pathways. Pretreatment with caspase-3, -8, and -9 inhibitors rescued the anti-proliferative effect of PR-171. Furthermore, pulse PR-171 treatment activated c-Jun-N-terminal kinase, a key-signaling molecule in proteasome inhibitor-induced apoptosis, and cleavage of poly-ADP-ribose polymerase, while abrogation of c-Jun-N-terminal kinase signaling with a dominant-negative c-Jun inhibited PR-171-induced effects. PR-171 displayed enhanced anti-proliferative activity compared to bortezomib in multiple myeloma cell lines and freshly isolated patient-derived CD138+ plasma cells, associated with enhanced phosphorylation of c-Jun-N-terminal kinase and capase-3, -8, and -9 activation. Lastly, PR-171 was a potent inhibitor of proliferation in a multiple myeloma cell line model resistant to bortezomib and in isolates from two patients, one with primary and the other with acquired bortezomib-resistance. Conclusions: These data indicate that PR-171 has enhanced activity against preclinical models of multiple myeloma, perhaps owing to its irreversible binding and subunit specificity, and provide a rationale for its translation into the clinic.
11
Zwergal, Andreas, Magdalena Lindner, Maximilian Grosch, and Marianne Dieterich. "In vivo neuroplasticity in vestibular animal models." Molecular and Cellular Neuroscience 120 (May 2022): 103721. http://dx.doi.org/10.1016/j.mcn.2022.103721.
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Benink, Hélène A., Craig A. Mandato, and William M. Bement. "Analysis of Cortical Flow Models In Vivo." Molecular Biology of the Cell 11, no. 8 (August 2000): 2553–63. http://dx.doi.org/10.1091/mbc.11.8.2553.
Abstract:
Cortical flow, the directed movement of cortical F-actin and cortical organelles, is a basic cellular motility process. Microtubules are thought to somehow direct cortical flow, but whether they do so by stimulating or inhibiting contraction of the cortical actin cytoskeleton is the subject of debate. Treatment ofXenopus oocytes with phorbol 12-myristate 13-acetate (PMA) triggers cortical flow toward the animal pole of the oocyte; this flow is suppressed by microtubules. To determine how this suppression occurs and whether it can control the direction of cortical flow, oocytes were subjected to localized manipulation of either the contractile stimulus (PMA) or microtubules. Localized PMA application resulted in redirection of cortical flow toward the site of application, as judged by movement of cortical pigment granules, cortical F-actin, and cortical myosin-2A. Such redirected flow was accelerated by microtubule depolymerization, showing that the suppression of cortical flow by microtubules is independent of the direction of flow. Direct observation of cortical F-actin by time-lapse confocal analysis in combination with photobleaching showed that cortical flow is driven by contraction of the cortical F-actin network and that microtubules suppress this contraction. The oocyte germinal vesicle serves as a microtubule organizing center inXenopus oocytes; experimental displacement of the germinal vesicle toward the animal pole resulted in localized flow away from the animal pole. The results show that 1) cortical flow is directed toward areas of localized contraction of the cortical F-actin cytoskeleton; 2) microtubules suppress cortical flow by inhibiting contraction of the cortical F-actin cytoskeleton; and 3) localized, microtubule-dependent suppression of actomyosin-based contraction can control the direction of cortical flow. We discuss these findings in light of current models of cortical flow.
13
Vignon, Anaïs, Lucie Salvador-Prince, Sylvain Lehmann, Véronique Perrier, and Joan Torrent. "Deconstructing Alzheimer’s Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?" International Journal of Molecular Sciences 22, no. 16 (August 16, 2021): 8769. http://dx.doi.org/10.3390/ijms22168769.
Abstract:
Discovered more than a century ago, Alzheimer’s disease (AD) is not only still present in our societies but has also become the most common dementia, with 50 million people worldwide affected by the disease. This number is expected to double in the next generation, and no cure is currently available to slow down or stop the disease progression. Recently, some advances were made due to the approval of the aducanumab treatment by the American Food and Drug Administration. The etiology of this human-specific disease remains poorly understood, and the mechanisms of its development have not been completely clarified. Several hypotheses concerning the molecular mechanisms of AD have been proposed, but the existing studies focus primarily on the two main markers of the disease: the amyloid β peptides, whose aggregation in the brain generates amyloid plaques, and the abnormally phosphorylated tau proteins, which are responsible for neurofibrillary tangles. These protein aggregates induce neuroinflammation and neurodegeneration, which, in turn, lead to cognitive and behavioral deficits. The challenge is, therefore, to create models that best reproduce this pathology. This review aims at gathering the different existing AD models developed in vitro, in cellulo, and in vivo. Many models have already been set up, but it is necessary to identify the most relevant ones for our investigations. The purpose of the review is to help researchers to identify the most pertinent disease models, from the most often used to the most recently generated and from simple to complex, explaining their specificities and giving concrete examples.
14
Michie, A. M., R. Nakagawa, and A. M. McCaig. "Murine models for chronic lymphocytic leukaemia." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1009–12. http://dx.doi.org/10.1042/bst0351009.
Abstract:
CLL (chronic lymphocytic leukaemia) is characterized by the clonal outgrowth of B-lymphocytes with the distinctive phenotype: CD19hiCD5+CD23+IgMlo. These malignant B-cells accumulate in the PB (peripheral blood) and lymphoid organs, and are generally arrested at the G0/G1-phase of cell cycle and display a resistance to apoptosis. To date, most of the CLL research has been carried out using PB samples obtained from patients with established CLL, which have proved instrumental in characterizing the disease. However, while CLL cells appear to have a defect in apoptosis in vivo, they rapidly undergo apoptosis ex vivo, suggesting that CLL cells are dependent on microenvironmental signals to enhance cell survival. One approach used to define the cellular and molecular events that govern CLL has been the development of murine models that replicate the human disease. As well as providing a deeper understanding of the potential triggers for CLL, these models provide preclinical in vivo systems to test novel therapies. The focus of the present review will be to highlight the recent advances in the development of mouse models for CLL.
15
Immarigeon, Clément, Sandra Bernat-Fabre, Emmanuelle Guillou, Alexis Verger, Elodie Prince, Mohamed A. Benmedjahed, Adeline Payet, et al. "Mediator complex subunit Med19 binds directly GATA transcription factors and is required with Med1 for GATA-driven gene regulation in vivo." Journal of Biological Chemistry 295, no. 39 (July 31, 2020): 13617–29. http://dx.doi.org/10.1074/jbc.ra120.013728.
Abstract:
The evolutionarily conserved multiprotein Mediator complex (MED) serves as an interface between DNA-bound transcription factors (TFs) and the RNA Pol II machinery. It has been proposed that each TF interacts with a dedicated MED subunit to induce specific transcriptional responses. But are these binary partnerships sufficient to mediate TF functions? We have previously established that the Med1 Mediator subunit serves as a cofactor of GATA TFs in Drosophila, as shown in mammals. Here, we observe mutant phenotype similarities between another subunit, Med19, and the Drosophila GATA TF Pannier (Pnr), suggesting functional interaction. We further show that Med19 physically interacts with the Drosophila GATA TFs, Pnr and Serpent (Srp), in vivo and in vitro through their conserved C-zinc finger domains. Moreover, Med19 loss of function experiments in vivo or in cellulo indicate that it is required for Pnr- and Srp-dependent gene expression, suggesting general GATA cofactor functions. Interestingly, Med19 but not Med1 is critical for the regulation of all tested GATA target genes, implying shared or differential use of MED subunits by GATAs depending on the target gene. Lastly, we show a direct interaction between Med19 and Med1 by GST pulldown experiments indicating privileged contacts between these two subunits of the MED middle module. Together, these findings identify Med19/Med1 as a composite GATA TF interface and suggest that binary MED subunit–TF partnerships are probably oversimplified models. We propose several mechanisms to account for the transcriptional regulation of GATA-targeted genes.
16
Mellström, Britt, Magali Savignac, Rosa Gomez-Villafuertes, and Jose R. Naranjo. "Ca2+-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models." Physiological Reviews 88, no. 2 (April 2008): 421–49. http://dx.doi.org/10.1152/physrev.00041.2005.
Abstract:
Calcium is the most universal signal used by living organisms to convey information to many different cellular processes. In this review we present well-known and recently identified proteins that sense and decode the calcium signal and are key elements in the nucleus to regulate the activity of various transcriptional networks. When possible, the review also presents in vivo models in which the genes encoding these calcium sensors-transducers have been modified, to emphasize the critical role of these Ca2+-operated mechanisms in many physiological functions.
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Jiménez-Heffernan, J. A., A. Cirugeda, M. A. Bajo, G. Del Peso, M. L. Pérez-Lozano, C. Perna, R. Selgas, and M. LÓpez-Cabrera. "Tissue Models of Peritoneal Fibrosis." International Journal of Artificial Organs 28, no. 2 (February 2005): 105–11. http://dx.doi.org/10.1177/039139880502800205.
Abstract:
Objective To evaluate the utility of peritoneal pathologic samples, unrelated to peritoneal dialysis (PD) treatment, for the study of peritoneal fibrosis and inflammation. Methods Comparative morphologic and immunohistochemical study of peritoneal pathologic samples unrelated to PD with peritoneal biopsies from PD patients with special emphasis on the expression of myofibroblastic and epithelial-to-mesenchymal transition markers. Results Regarding morphology, PD-related simple fibrosis was less cellular, with greater stromal hyalinization, determining a homogeneous, hypocellular aspect of the submesothelium. In contrast, non-PD fibrosis was more cellular with an extracellular matrix showing a dense and fibrillar quality with wide bundles of collagen. Hylinazing vasculopathy was only present in PD samples. Myofibroblastic differentiation and epithelial-to-mesenchymal transition were common findings in all situations of peritoneal fibrosis. Calponin and calretinin are useful cellular markers to study such fibrogenic mechanisms and correlate with other well-known markers such as α-SMA and cytokeratins. Their expression was much more intense in those samples showing acute inflammation (peritonitis). Conclusions Non-PD models of peritoneal fibrosis seem very useful to evaluate important features of human peritoneal pathology such us fibrogenesis, and inflammation. Fibrogenic events such as myofibroblastic differentiation and epithelial-to-mesenchymal transition are evident in these tissue samples allowing us to use them as an accessible source for in vivo and ex vivo studies. Both events show their maximal expression in situations of acute inflammation supporting the important role that peritonitis episodes play in the progression of fibrosis.
18
Yu, Pengfei, Zhongping Duan, Shuang Liu, Ivan Pachon, Jianxing Ma, George Hemstreet, and Yuanyuan Zhang. "Drug-Induced Nephrotoxicity Assessment in 3D Cellular Models." Micromachines 13, no. 1 (December 21, 2021): 3. http://dx.doi.org/10.3390/mi13010003.
Abstract:
The kidneys are often involved in adverse effects and toxicity caused by exposure to foreign compounds, chemicals, and drugs. Early predictions of these influences are essential to facilitate new, safe drugs to enter the market. However, in current drug treatments, drug-induced nephrotoxicity accounts for 1/4 of reported serious adverse reactions, and 1/3 of them are attributable to antibiotics. Drug-induced nephrotoxicity is driven by multiple mechanisms, including altered glomerular hemodynamics, renal tubular cytotoxicity, inflammation, crystal nephropathy, and thrombotic microangiopathy. Although the functional proteins expressed by renal tubules that mediate drug sensitivity are well known, current in vitro 2D cell models do not faithfully replicate the morphology and intact renal tubule function, and therefore, they do not replicate in vivo nephrotoxicity. The kidney is delicate and complex, consisting of a filter unit and a tubular part, which together contain more than 20 different cell types. The tubular epithelium is highly polarized, and maintaining cellular polarity is essential for the optimal function and response to environmental signals. Cell polarity depends on the communication between cells, including paracrine and autocrine signals, as well as biomechanical and chemotaxis processes. These processes affect kidney cell proliferation, migration, and differentiation. For drug disposal research, the microenvironment is essential for predicting toxic reactions. This article reviews the mechanism of drug-induced kidney injury, the types of nephrotoxicity models (in vivo and in vitro models), and the research progress related to drug-induced nephrotoxicity in three-dimensional (3D) cellular culture models.
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Doege, Holger, and Andreas Stahl. "Protein-Mediated Fatty Acid Uptake: Novel Insights from In Vivo Models." Physiology 21, no. 4 (August 2006): 259–68. http://dx.doi.org/10.1152/physiol.00014.2006.
Abstract:
Long-chain fatty acids are both important metabolites as well as signaling molecules. Fatty acid transport proteins are key mediators of cellular fatty acid uptake and recent transgenic and knockout animal models have provided new insights into their contribution to energy homeostasis and to pathological processes, including obesity and insulin desensitization.
20
Alfonsetti, Margherita, Vanessa Castelli, Michele d’Angelo, Elisabetta Benedetti, Marcello Allegretti, Barbara Barboni, and Annamaria Cimini. "Looking for In Vitro Models for Retinal Diseases." International Journal of Molecular Sciences 22, no. 19 (September 25, 2021): 10334. http://dx.doi.org/10.3390/ijms221910334.
Abstract:
Retina is a layered structure of the eye, composed of different cellular components working together to produce a complex visual output. Because of its important role in visual function, retinal pathologies commonly represent the main causes of visual injury and blindness in the industrialized world. It is important to develop in vitro models of retinal diseases to use them in first screenings before translating in in vivo experiments and clinics. For this reason, it is important to develop bidimensional (2D) models that are more suitable for drug screening and toxicological studies and tridimensional (3D) models, which can replicate physiological conditions, for investigating pathological mechanisms leading to visual loss. This review provides an overview of the most common retinal diseases, relating to in vivo models, with a specific focus on alternative 2D and 3D in vitro models that can replicate the different cellular and matrix components of retinal layers, as well as injury insults that induce retinal disease and loss of the visual function.
21
Schnichels, Sven, Tobias Kiebler, José Hurst, Ana M. Maliha, Marina Löscher, H. Burkhard Dick, Karl-Ulrich Bartz-Schmidt, and Stephanie C. Joachim. "Retinal Organ Cultures as Alternative Research Models." Alternatives to Laboratory Animals 47, no. 1 (March 2019): 19–29. http://dx.doi.org/10.1177/0261192919840092.
Abstract:
Ex vivo organ cultures represent unique research models, as they combine the advantages of cell cultures with those of animal models. Being able to mimic in vivo situations through the use of organ cultures provides an excellent opportunity to investigate cellular processes, molecular pathways and cell–cell interactions, as well as structural and synaptic organisation. Human and animal organ cultures are now well established and comprise sensitive, easy-to-manipulate experimental systems that raise minimal ethical concerns. The eye, in particular, is a very complex organ that is not easy to reproduce in vitro. However, a lot of research has been dedicated to the development of suitable ocular organ cultures. This review covers the various ex vivo retinal organ culture systems available for use in ophthalmology research and compares them with commonly used animal models. In particular, bovine and porcine retinal organ culture systems are described, because the size, anatomy, physiology and vessel morphology of bovine and porcine eyes are similar to the human eye in an undisputed way, thus making them good models. In addition, these animals are widely used by the food industry and the eyes are considered surplus material. A short overview of murine, rat, rabbit, cat, canine and simian retinal organ cultures is also provided.
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DeSimone, Alec M., Justin Cohen, Monkol Lek, and Angela Lek. "Cellular and animal models for facioscapulohumeral muscular dystrophy." Disease Models & Mechanisms 13, no. 10 (October 1, 2020): dmm046904. http://dx.doi.org/10.1242/dmm.046904.
Abstract:
ABSTRACTFacioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and presents with weakness of the facial, scapular and humeral muscles, which frequently progresses to the lower limbs and truncal areas, causing profound disability. Myopathy results from epigenetic de-repression of the D4Z4 microsatellite repeat array on chromosome 4, which allows misexpression of the developmentally regulated DUX4 gene. DUX4 is toxic when misexpressed in skeletal muscle and disrupts several cellular pathways, including myogenic differentiation and fusion, which likely underpins pathology. DUX4 and the D4Z4 array are strongly conserved only in primates, making FSHD modeling in non-primate animals difficult. Additionally, its cytotoxicity and unusual mosaic expression pattern further complicate the generation of in vitro and in vivo models of FSHD. However, the pressing need to develop systems to test therapeutic approaches has led to the creation of multiple engineered FSHD models. Owing to the complex genetic, epigenetic and molecular factors underlying FSHD, it is difficult to engineer a system that accurately recapitulates every aspect of the human disease. Nevertheless, the past several years have seen the development of many new disease models, each with their own associated strengths that emphasize different aspects of the disease. Here, we review the wide range of FSHD models, including several in vitro cellular models, and an array of transgenic and xenograft in vivo models, with particular attention to newly developed systems and how they are being used to deepen our understanding of FSHD pathology and to test the efficacy of drug candidates.
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Krauss, Sybille, and Ina Vorberg. "PrionsEx Vivo: What Cell Culture Models Tell Us about Infectious Proteins." International Journal of Cell Biology 2013 (2013): 1–14. http://dx.doi.org/10.1155/2013/704546.
Abstract:
Prions are unconventional infectious agents that are composed of misfolded aggregated prion protein. Prions replicate their conformation by template-assisted conversion of the endogenous prion protein PrP. Templated conversion of soluble proteins into protein aggregates is also a hallmark of other neurodegenerative diseases. Alzheimer’s disease or Parkinson’s disease are not considered infectious diseases, although aggregate pathology appears to progress in a stereotypical fashion reminiscent of the spreading behavior ofmammalian prions. While basic principles of prion formation have been studied extensively, it is still unclear what exactly drives PrP molecules into an infectious, self-templating conformation. In this review, we discuss crucial steps in the life cycle of prions that have been revealed inex vivomodels. Importantly, the persistent propagation of prions in mitotically active cells argues that cellular processes are in place that not only allow recruitment of cellular PrP into growing prion aggregates but also enable the multiplication of infectious seeds that are transmitted to daughter cells. Comparison of prions with other protein aggregates demonstrates that not all the characteristics of prions are equally shared by prion-like aggregates. Future experiments may reveal to which extent aggregation-prone proteins associated with other neurodegenerative diseases can copy the replication strategies of prions.
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Firkova, E. I. "In vivo animal models in periodontal research - focus on rodents." BULGARIAN JOURNAL OF VETERINARY MEDICINE 24, no. 2 (2021): 167–75. http://dx.doi.org/10.15547/bjvm.2019-0056.
Abstract:
Periodontal research has developed very fast in the last two decades. Although at this stage of science a lot of genetic and molecular-based trials are performed in order to elucidate the complex etiology, pathophysiology, biofilm-host interactions and responses on genetic and cellular level, in vivo animal models are still used. In many ways, in vivo experiments are superior to in vitro tests when the dynamics of the immune-inflammatory nature of the periodontal disease and peri-implantitis and the specific healing of soft and hard tissues is concerned. Screening the efficacy, mechanisms of action and application of different biomaterials requires in vivo experiments, be-fore the data translation to clinical settings. A number of small animals like rodents and large species like dogs and nonhuman primates are involved in periodontal research. As live creatures are used, the design of the studies must be well defined, with regard to the type of the animals, most suitable for the tested hypothesis, observation period, sample size, study power, critical size defects, and specific testing sites.
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Erice, Oihane, Adrian Vallejo, Mariano Ponz-Sarvise, Michael Saborowski, Arndt Vogel, Diego F. Calvisi, Anna Saborowski, and Silvestre Vicent. "Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research." Cancers 11, no. 12 (November 26, 2019): 1868. http://dx.doi.org/10.3390/cancers11121868.
Abstract:
Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system.
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Occhialini, Alessandra, Dirk Hofreuter, Christoph-Martin Ufermann, Sascha Al Dahouk, and Stephan Köhler. "The Retrospective on Atypical Brucella Species Leads to Novel Definitions." Microorganisms 10, no. 4 (April 14, 2022): 813. http://dx.doi.org/10.3390/microorganisms10040813.
Abstract:
The genus Brucella currently comprises twelve species of facultative intracellular bacteria with variable zoonotic potential. Six of them have been considered as classical, causing brucellosis in terrestrial mammalian hosts, with two species originated from marine mammals. In the past fifteen years, field research as well as improved pathogen detection and typing have allowed the identification of four new species, namely Brucella microti, Brucella inopinata, Brucella papionis, Brucella vulpis, and of numerous strains, isolated from a wide range of hosts, including for the first time cold-blooded animals. While their genome sequences are still highly similar to those of classical strains, some of them are characterized by atypical phenotypes such as higher growth rate, increased resistance to acid stress, motility, and lethality in the murine infection model. In our review, we provide an overview of state-of-the-art knowledge about these novel Brucella sp., with emphasis on their phylogenetic positions in the genus, their metabolic characteristics, acid stress resistance mechanisms, and their behavior in well-established in cellulo and in vivo infection models. Comparison of phylogenetic classification and phenotypical properties between classical and novel Brucella species and strains finally lead us to propose a more adapted terminology, distinguishing between core and non-core, and typical versus atypical brucellae, respectively.
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Azuma, Mitsuyoshi, Thomas R. Shearer, Takahiro Matsumoto, Larry L. David, and Takashi Murach. "Calpain II in two in vivo models of sugar cataract." Experimental Eye Research 51, no. 4 (October 1990): 393–401. http://dx.doi.org/10.1016/0014-4835(90)90151-j.
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Auer, Ewald. "P4-264: In Vitro and in Vivo Hypothermia Models." Alzheimer's & Dementia 12 (July 2016): P1131—P1132. http://dx.doi.org/10.1016/j.jalz.2016.06.2375.
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Picchio, Vittorio, Erica Floris, Yuriy Derevyanchuk, Claudia Cozzolino, Elisa Messina, Francesca Pagano, Isotta Chimenti, and Roberto Gaetani. "Multicellular 3D Models for the Study of Cardiac Fibrosis." International Journal of Molecular Sciences 23, no. 19 (October 1, 2022): 11642. http://dx.doi.org/10.3390/ijms231911642.
Abstract:
Ex vivo modelling systems for cardiovascular research are becoming increasingly important in reducing lab animal use and boosting personalized medicine approaches. Integrating multiple cell types in complex setups adds a higher level of significance to the models, simulating the intricate intercellular communication of the microenvironment in vivo. Cardiac fibrosis represents a key pathogenetic step in multiple cardiovascular diseases, such as ischemic and diabetic cardiomyopathies. Indeed, allowing inter-cellular interactions between cardiac stromal cells, endothelial cells, cardiomyocytes, and/or immune cells in dedicated systems could make ex vivo models of cardiac fibrosis even more relevant. Moreover, culture systems with 3D architectures further enrich the physiological significance of such in vitro models. In this review, we provide a summary of the multicellular 3D models for the study of cardiac fibrosis described in the literature, such as spontaneous microtissues, bioprinted constructs, engineered tissues, and organs-on-chip, discussing their advantages and limitations. Important discoveries on the physiopathology of cardiac fibrosis, as well as the screening of novel potential therapeutic molecules, have been reported thanks to these systems. Future developments will certainly increase their translational impact for understanding and modulating mechanisms of cardiac fibrosis even further.
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White, Nicole M., Dechen Jiang, James D. Burgess, Ilya R. Bederman, Stephen F. Previs, and Thomas J. Kelley. "Altered cholesterol homeostasis in cultured and in vivo models of cystic fibrosis." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 2 (February 2007): L476—L486. http://dx.doi.org/10.1152/ajplung.00262.2006.
Abstract:
Determining how the regulation of cellular processes is impacted in cystic fibrosis (CF) is fundamental to understanding disease pathology and to identifying new therapeutic targets. In this study, unesterified cholesterol accumulation is observed in lung and trachea sections obtained from CF patients compared with non-CF tissues, suggesting an inherent flaw in cholesterol processing. An alternate staining method utilizing a fluorescent cholesterol probe also indicates improper lysosomal storage of cholesterol in CF cells. Excess cholesterol is also manifested by a significant increase in plasma membrane cholesterol content in both cultured CF cells and in nasal tissue excised from cftr −/− mice. Impaired intracellular cholesterol movement is predicted to stimulate cholesterol synthesis, a hypothesis supported by the observation of increased de novo cholesterol synthesis in lung and liver of cftr −/− mice compared with controls. Furthermore, pharmacological inhibition of cholesterol transport is sufficient to cause CF-like elevation in cytokine production in wild-type cells in response to bacterial challenge but has no effect in CF cells. These data demonstrate via multiple methods in both cultured and in vivo models that cellular cholesterol homeostasis is inherently altered in CF. This perturbation of cholesterol homeostasis represents a potentially important process in CF pathogenesis.
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Slatova, L. N., T. A. Fedorina, and E. P. Shatunova. "Experimental models of myocardial ischemia: classical approaches and innovations (review)." Siberian Journal of Clinical and Experimental Medicine 39, no. 1 (April 4, 2024): 18–27. http://dx.doi.org/10.29001/2073-8552-2024-39-1-18-27.
Abstract:
Myocardial ischemia is the basis for many acute and chronic conditions with great social significance. Therefore, experimental models that describe ischemia development in humans are necessary for a better understanding of the pathophysiology of these conditions and the development of medical and surgical methods of treatment.Aim: To compare current approaches to experimental modeling of myocardial ischemia considering the pathogenetic features of the simulated processes. The manuscript describes the main experimental models of myocardial ischemia: in vitro cellular models, ex vivo isolated heart models, in vivo animal models, the principal components of the ‘heart-on-chip’ model and the possibilities of in silico modeling. The criteria for choosing a specific model of ischemia by pathophysiological approach, advantages and limitations of the models are considered.
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Bumann, Dirk. "T cell receptor-transgenic mouse models for studying cellular immune responses toSalmonellain vivo." FEMS Immunology & Medical Microbiology 37, no. 2-3 (July 2003): 105–9. http://dx.doi.org/10.1016/s0928-8244(03)00064-6.
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Wang, Eddy Hsi Chun, Rebecca Barresi-Thornton, Li-Chi Chen, Maryanne Makredes Senna, I.-Chien Liao, Ying Chen, Qian Zheng, and Charbel Bouez. "The Development of Human Ex Vivo Models of Inflammatory Skin Conditions." International Journal of Molecular Sciences 24, no. 24 (December 8, 2023): 17255. http://dx.doi.org/10.3390/ijms242417255.
Abstract:
Traditional research in inflammatory dermatoses has relied on animal models and reconstructed human epidermis to study these conditions. However, these models are limited in replicating the complexity of real human skin and reproducing the intricate pathological changes in skin barrier components and lipid profiles. To address this gap, we developed experimental models that mimic various human inflammatory skin phenotypes. Human ex vivo skins were stimulated with various triggers, creating models for inflammation-induced angiogenesis, irritation response, and chronic T-cell activation. We assessed the alterations in skin morphology, cellular infiltrates, cytokine production, and epidermal lipidomic profiles. In the pro-angiogenesis model, we observed increased mast cell degranulation and elevated levels of angiogenic growth factors. Both the irritant and chronic inflammation models exhibited severe epidermal disruption, along with macrophage infiltration, leukocyte exocytosis, and heightened cytokine levels. Lipidomic analysis revealed minor changes in the pro-angiogenesis model, whereas the chronic inflammation and irritant models exhibited significant decreases in barrier essential ceramide subclasses and a shift toward shorter acyl chain lengths (<C18), indicating skin barrier instability. Additionally, the irritant and chronic inflammation models are responsive to immunosuppressants. These models hold promise for advancing scientific understanding and the development of therapeutic and skincare solutions for individuals afflicted by compromised skin conditions.
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Grant, A. L., and D. E. Gerrard. "Cellular and molecular approaches for altering muscle growth and development." Canadian Journal of Animal Science 78, no. 4 (December 1, 1998): 493–502. http://dx.doi.org/10.4141/a98-090.
Abstract:
Understanding the cellular and molecular processes involved in the development of muscle is necessary to develop new strategies for improving the efficiency of meat-animal production. The objectives of this paper are to review some of the processes of muscle development important to meat animal production, including meat quality, and to identify potential cellular and molecular biological approaches to alter these developmental processes. Some of the processes by which muscle develops can be exploited in order to develop in vivo models for further study of muscle growth. Cell-mediated gene transfer and direct DNA injection are among the many techniques that can be used to develop in vivo animal models, and these models can be developed in meat-producing species. Many of these models will undoubtedly lead to the development of strategies to enhance meat-animal production. Key words: Myogenesis, gene transfer, DNA, muscle fiber, meat quality
35
Lee, Young Jae. "Knockout Mouse Models for Peroxiredoxins." Antioxidants 9, no. 2 (February 22, 2020): 182. http://dx.doi.org/10.3390/antiox9020182.
Abstract:
Peroxiredoxins (PRDXs) are members of a highly conserved peroxidase family and maintain intracellular reactive oxygen species (ROS) homeostasis. The family members are expressed in most organisms and involved in various biological processes, such as cellular protection against ROS, inflammation, carcinogenesis, atherosclerosis, heart diseases, and metabolism. In mammals, six PRDX members have been identified and are subdivided into three subfamilies: typical 2-Cys (PRDX1, PRDX2, PRDX3, and PRDX4), atypical 2-Cys (PRDX5), and 1-Cys (PRDX6) subfamilies. Knockout mouse models of PRDXs have been developed to investigate their in vivo roles. This review presents an overview of the knockout mouse models of PRDXs with emphases on the biological and physiological changes of these model mice.
36
Bassi, Giada, Maria Aurora Grimaudo, Silvia Panseri, and Monica Montesi. "Advanced Multi-Dimensional Cellular Models as Emerging Reality to Reproduce In Vitro the Human Body Complexity." International Journal of Molecular Sciences 22, no. 3 (January 26, 2021): 1195. http://dx.doi.org/10.3390/ijms22031195.
Abstract:
A hot topic in biomedical science is the implementation of more predictive in vitro models of human tissues to significantly improve the knowledge of physiological or pathological process, drugs discovery and screening. Bidimensional (2D) culture systems still represent good high-throughput options for basic research. Unfortunately, these systems are not able to recapitulate the in vivo three-dimensional (3D) environment of native tissues, resulting in a poor in vitro–in vivo translation. In addition, intra-species differences limited the use of animal data for predicting human responses, increasing in vivo preclinical failures and ethical concerns. Dealing with these challenges, in vitro 3D technological approaches were recently bioengineered as promising platforms able to closely capture the complexity of in vivo normal/pathological tissues. Potentially, such systems could resemble tissue-specific extracellular matrix (ECM), cell–cell and cell–ECM interactions and specific cell biological responses to mechanical and physical/chemical properties of the matrix. In this context, this review presents the state of the art of the most advanced progresses of the last years. A special attention to the emerging technologies for the development of human 3D disease-relevant and physiological models, varying from cell self-assembly (i.e., multicellular spheroids and organoids) to the use of biomaterials and microfluidic devices has been given.
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Goodwin, T. J., L. Coate-Li, R. M. Linnehan, and T. G. Hammond. "Selected Contribution: A three-dimensional model for assessment of in vitro toxicity inBalaena mysticetusrenal tissue." Journal of Applied Physiology 89, no. 6 (December 1, 2000): 2508–17. http://dx.doi.org/10.1152/jappl.2000.89.6.2508.
Abstract:
This study established two- and three-dimensional renal proximal tubular cell cultures of the endangered species bowhead whale ( Balaena mysticetus), developed SV40-transfected cultures, and cloned the 61-amino acid open reading frame for the metallothionein protein, the primary binding site for heavy metal contamination in mammals. Microgravity research, modulations in mechanical culture conditions (modeled microgravity), and shear stress have spawned innovative approaches to understanding the dynamics of cellular interactions, gene expression, and differentiation in several cellular systems. These investigations have led to the creation of ex vivo tissue models capable of serving as physiological research analogs for three-dimensional cellular interactions. These models are enabling studies in immune function, tissue modeling for basic research, and neoplasia. Three-dimensional cellular models emulate aspects of in vivo cellular architecture and physiology and may facilitate environmental toxicological studies aimed at elucidating biological functions and responses at the cellular level. Marine mammals occupy a significant ecological niche (72% of the Earth's surface is water) in terms of the potential for information on bioaccumulation and transport of terrestrial and marine environmental toxins in high-order vertebrates. Few ex vivo models of marine mammal physiology exist in vitro to accomplish the aforementioned studies. Techniques developed in this investigation, based on previous tissue modeling successes, may serve to facilitate similar research in other marine mammals.
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Bataille, Adeline, Christelle Le Gall, Laurent Misery, and Matthieu Talagas. "Merkel Cells Are Multimodal Sensory Cells: A Review of Study Methods." Cells 11, no. 23 (November 29, 2022): 3827. http://dx.doi.org/10.3390/cells11233827.
Abstract:
Merkel cells (MCs) are rare multimodal epidermal sensory cells. Due to their interactions with slowly adapting type 1 (SA1) Aβ low-threshold mechanoreceptor (Aβ-LTMRs) afferents neurons to form Merkel complexes, they are considered to be part of the main tactile terminal organ involved in the light touch sensation. This function has been explored over time by ex vivo, in vivo, in vitro, and in silico approaches. Ex vivo studies have made it possible to characterize the topography, morphology, and cellular environment of these cells. The interactions of MCs with surrounding cells continue to be studied by ex vivo but also in vitro approaches. Indeed, in vitro models have improved the understanding of communication of MCs with other cells present in the skin at the cellular and molecular levels. As for in vivo methods, the sensory role of MC complexes can be demonstrated by observing physiological or pathological behavior after genetic modification in mouse models. In silico models are emerging and aim to elucidate the sensory coding mechanisms of these complexes. The different methods to study MC complexes presented in this review may allow the investigation of their involvement in other physiological and pathophysiological mechanisms, despite the difficulties in exploring these cells, in particular due to their rarity.
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Bokova, U. A., M. S. Tretyakova, A. A. Schegoleva, and E. V. Denisov. "<i>In vivo</i> models in cancer research." Advances in Molecular Oncology 10, no. 2 (July 10, 2023): 8–16. http://dx.doi.org/10.17650/2313-805x-2023-10-2-8-16.
Abstract:
Cancers are one of the leading causes of mortality in the world. Cellular and physiological mechanisms of cancer development remain not well defined. In vivo models are an attractive approach for understanding of cancer origin and progression. This review presents current state of experimental in vivo systems including syngeneic models, patient-derived xenografts (PDX), cell line-derived xenografts (CDX) and various animals – humanized and genetically engineered models (GEM). These models provide opportunities for developing patients’ avatars, lifetime visualization of tumor migration and invasion at the organism level, and the evaluation of new therapeutic methods aimed at primary tumors, metastases, and cancer prevention. We also discuss the problems of choosing the optimal model and potential solutions for their overcoming.
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Liu, Ye, Zahra Mohri, Wissal Alsheikh, and Umber Cheema. "The Role of Biomimetic Hypoxia on Cancer Cell Behaviour in 3D Models: A Systematic Review." Cancers 13, no. 6 (March 16, 2021): 1334. http://dx.doi.org/10.3390/cancers13061334.
Abstract:
The development of biomimetic, human tissue models is recognized as being an important step for transitioning in vitro research findings to the native in vivo response. Oftentimes, 2D models lack the necessary complexity to truly recapitulate cellular responses. The introduction of physiological features into 3D models informs us of how each component feature alters specific cellular response. We conducted a systematic review of research papers where the focus was the introduction of key biomimetic features into in vitro models of cancer, including 3D culture and hypoxia. We analysed outcomes from these and compiled our findings into distinct groupings to ascertain which biomimetic parameters correlated with specific responses. We found a number of biomimetic features which primed cancer cells to respond in a manner which matched in vivo response.
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Wondisford, Fredric E. "Thyroid Hormone Action: Insight from Transgenic Mouse Models." Journal of Investigative Medicine 51, no. 4 (July 2003): 215–20. http://dx.doi.org/10.1177/108155890305100422.
Abstract:
Thyroid hormone receptors (TRs) are cellular homologues of the viral erythroblastic leukemia oncogene (v-erbA). TRs (c-crbA isoforms) are derived from two separate gene loci in mammals: a and p. Through a series of knockout experiments in mice in which one or several of the TR isoforms were deleted, it has been demonstrated that the TR-β isoforms control central regulation of thyroid-stimulating hormone. Of these isoforms, TR-β2 is the most important in mediating negative feedback control of the hypothalamic-pituitary-thyroid axis. Further analysis of TR knockout animals revealed, however, that they exhibited a much milder overall phenotype than hypothyroid animals, indicating that receptor loss was not equivalent to ligand loss in vivo. To understand this apparent paradox, we generated animals expressing a non-T3 binding receptor (Δ337T) from the TR-β allele. These mice displayed a complete hypothyroid phenotype, demonstrating that the unliganded TR mediates the effect of hypothyroidism. Because this mutant TR constitutively binds to nuclear coreprssors, it also suggests that this class of proteins is essential for mediating hypothyroidism in vivo.
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Luo, J. J., C. D. Young, H. M. Zhou, and X. J. Wang. "Mouse Models for Studying Oral Cancer: Impact in the Era of Cancer Immunotherapy." Journal of Dental Research 97, no. 6 (April 12, 2018): 683–90. http://dx.doi.org/10.1177/0022034518767635.
Abstract:
Model systems for oral cancer research have progressed from tumor epithelial cell cultures to in vivo systems that mimic oral cancer genetics, pathological characteristics, and tumor-stroma interactions of oral cancer patients. In the era of cancer immunotherapy, it is imperative to use model systems to test oral cancer prevention and therapeutic interventions in the presence of an immune system and to discover mechanisms of stromal contributions to oral cancer carcinogenesis. Here, we review in vivo mouse model systems commonly used for studying oral cancer and discuss the impact these models are having in advancing basic mechanisms, chemoprevention, and therapeutic intervention of oral cancer while highlighting recent discoveries concerning the role of immune cells in oral cancer. Improvements to in vivo model systems that highly recapitulate human oral cancer hold the key to identifying features of oral cancer initiation, progression, and invasion as well as molecular and cellular targets for prevention, therapeutic response, and immunotherapy development.
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Dong, Jinghui, Raquel Revilla-Sanchez, Stephen Moss, and Philip G. Haydon. "Multiphoton in vivo imaging of amyloid in animal models of Alzheimer’s disease." Neuropharmacology 59, no. 4-5 (September 2010): 268–75. http://dx.doi.org/10.1016/j.neuropharm.2010.04.007.
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Muelling, Christoph KW, Ulrike Nebel, and Rya-Yvonne Wuestenberg. "Innovative in vitro and ex vivo models for studying bovine hoof biology." Proceedings of the British Society of Animal Science 2007 (April 2007): 266. http://dx.doi.org/10.1017/s1752756200021694.
Abstract:
Research into the biology and physiopathology of the bovine claw has become interdisciplinary employing epidemiology, cellular and molecular biology. Foot disorders in cattle are a global problem causing substantial economic losses to farmers. New hypotheses demonstrate possible links between systemic problems and local damage in the claw. Tissue explant and cell culture studies have already provided important insights into regulation of differentiation in healthy and diseased claw tissue (Hendry et al 1997, 2003; Nebel et al 2002, 2004). Detailed knowledge of the links between systemic events and the claw tissue as well as knowledge on the local regulatory cascades in response to metabolic and biomechanical challenges provide the key to understanding of the development of claw diseases. The development and experimental application of novel organotypic in vitro culture systems and an ex vivo isolated haemoperfused distal cow limb model (Wüstenberg 2004) was a major task and outcome of the EU framework 5 project Lamecow (http://www.abdn.ac.uk/lamecow).
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Dubey, Anubhav, Samra Samra, Vikram Kumar Sahu, Sribatsa Lanchhana Dash, and Amit Mishra. "A Screening Models of (In Vivo And In Vitro) Used for the Study of Hepatoprotective Agents." Journal of Advanced Zoology 44, no. 3 (October 9, 2023): 173–87. http://dx.doi.org/10.17762/jaz.v44i3.578.
Abstract:
In order to evaluate hepatoprotective function, both in vitro and in vivo liver or hepatoprotective models have been constructed in the past. These methods examine a drug's potential to prevent or minimize liver damage in test animals. To express their effectiveness and safety in humans, new drugs must first travel through a number of developmental phases, beginning with the identification of their pharmacological characteristics in cellular and animal models. In the medical literature, there are many methods for measuring hepatoprotective efficacy in vivo and in vitro. Fresh hepatocytes are exposed to hepatotoxin treatment in in vitro models, and the effects of the test chemical on those cells are examined. To elicit liver damage in test animals, dangerous dosages of an identified hepatotoxin are administered in in vivo models. The test material is provided before, after, and simultaneously with the toxin treatment. Hepatitis in Long Evans and other chemical agents are commonly exploited to generate hepatotoxicity in experimental animals for the evaluation of hepatoprotective medications. Cinnamon rats, liver cirrhosis and necrosis, hepatic fibrosis brought on by carbon tetrachloride in rats, liver cirrhosis brought on by galactosamine, inhibition of proline hydroxylation, trans-heptic investigations model in dogs, etc. The many forms of in vivo and in vitro hepatoprotective screening models are explained in this article.
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Gulyaeva, N. V., N. V. Bobkova, N. G. Kolosova, A. N. Samokhin, M. Yu Stepanichev, and N. A. Stefanova. "Molecular and cellular mechanisms of sporadic Alzheimer’s disease: Studies on rodent models in vivo." Biochemistry (Moscow) 82, no. 10 (October 2017): 1088–102. http://dx.doi.org/10.1134/s0006297917100029.
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Huang, Lieven, Tobias D. Merson, and James A. Bourne. "In vivo whole brain, cellular and molecular imaging in nonhuman primate models of neuropathology." Neuroscience & Biobehavioral Reviews 66 (July 2016): 104–18. http://dx.doi.org/10.1016/j.neubiorev.2016.04.009.
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McGarrity-Cottrell, Connor, Katie Myers, Mark Dunning, Veejay Bagga, Saurabh Sinna, Yahia Al-Tamimi, Ola Rominiyi, and Spencer Collis. "DEfiNING SPATIAL HETEROGENEITY OF A NOVEL LIVING BIOBANK OF POST-SURGICAL RESIDUAL GLIOBLASTOMA TO DEVELOP STRATEGIES FOR TARGETED THERAPY." Neuro-Oncology 25, Supplement_3 (September 16, 2023): iii14. http://dx.doi.org/10.1093/neuonc/noad147.055.
Abstract:
Abstract AIMS Glioblastoma is the most common cancer arising within the brain accounting for >2,000 deaths/year in the UK. Current standard-of-care therapy consists of maximal safe surgical resection followed by radiochemotherapy which activates the cellular DNA damage response (DDR). However, disease prognosis remains poor (median OS ~12-15 months). This stagnation in the development and clinical translation of novel therapeutics is largely attributed to extensive inter- and intra-tumoral heterogeneity and resistant glioma stem cell (GSC) niches. Traditionally, primary ex vivo and in vivo models of glioblastoma have been generated from the resected tumour mass potentially omitting the post-surgical residual tumour cells that give rise to disease recurrence and morbidity. METHOD Multiple parallel primary ex vivo GSC cell models were generated from anatomically discrete regions of en-bloc partial lobectomy glioblastoma specimens to produce 3D models of resected (tumour “core”) and typically residual (distal invasive tumour “edge”) GSC niches. These models were characterised using an array of biomolecular techniques and 3D based assays. RESULTS Preliminary RNA-seq analyses revealed largely divergent transcriptional landscapes for resected vs residual GSCs and protein expression/immunofluorescence analyses also identified key differences in GSC and DDR ex- pression, and subsequent cellular responses to current standard-of-care radio-chemotherapy regimens. CONCLUSIONS These data reveal phenotypic relationships between GSC “stemness” and DDR activity, therefore highlighting the potential clinical relevance of our novel parallel resected and residual ex vivo glioblastoma models. Characterisation of further models from within our 3D GSC biobank will also aid evaluation of novel therapeutics capable of targeting post-surgical GSC subpopulations leading to improved disease outcomes.
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Wanigasekara, Janith, Lara J. Carroll, Patrick J. Cullen, Brijesh Tiwari, and James F. Curtin. "Three-Dimensional (3D) in vitro cell culture protocols to enhance glioblastoma research." PLOS ONE 18, no. 2 (February 8, 2023): e0276248. http://dx.doi.org/10.1371/journal.pone.0276248.
Abstract:
Three-dimensional (3D) cell culture models can help bridge the gap between in vitro cell cultures and in vivo responses by more accurately simulating the natural in vivo environment, shape, tissue stiffness, stressors, gradients and cellular response while avoiding the costs and ethical concerns associated with animal models. The inclusion of the third dimension in 3D cell culture influences the spatial organization of cell surface receptors that interact with other cells and imposes physical restrictions on cells in compared to Two-dimensional (2D) cell cultures. Spheroids’ distinctive cyto-architecture mimics in vivo cellular structure, gene expression, metabolism, proliferation, oxygenation, nutrition absorption, waste excretion, and drug uptake while preserving cell–extracellular matrix (ECM) connections and communication, hence influencing molecular processes and cellular phenotypes. This protocol describes the in vitro generation of tumourspheroids using the low attachment plate, hanging drop plate, and cellusponge natural scaffold based methods. The expected results from these protocols confirmed the ability of all these methods to create uniform tumourspheres.
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Barth, Matthew John, Gopichand Pendurti, Cory Mavis, Natalie Czuczman, Jospeh J. Skitzki, Francisco J. Hernandez-Ilizaliturri, and Myron Stefan Czuczman. "Preclinical activity of ofatumumab (OFA) in mantle cell lymphoma (MCL) in vitro, ex vivo, and in vivo models." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e18537-e18537. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e18537.
Abstract:
e18537 Background: MCL is characterized by an aggressive clinical course and inevitable development of refractory disease despite early intervention that often includes: immunotherapy (e.g., rituximab), multi-agent induction chemotherapy and consolidation with high dose chemotherapy and autologous stem cell transplant in first remission. OFA is a fully human anti-CD20 mAb targeting a novel membrane-proximal epitope on CD20. To characterize the activity of ofatumumab in MCL, we conducted pre-clinical studies in cell lines, primary tumor cells derived from MCL patients and a MCL bearing severe combined immunodeficiency (SCID) mouse model. Methods: Antibody-dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) assays were performed in 51Cr labeled Mino, Jeko, Rec-1 and Z-138 cells comparing RTX or OFA. Primary tumor cells were exposed ex vivo to OFA or RTX with human serum, differences in cell viability were determined by Cell Titer Glo assay. Expression of CD20 and complement inhibitory proteins (CIPs) CD55 and CD59 was determined by Imagestream analysis and Western blot. SCID mice were inoculated SQ with 10x106 Z-138 cells. Once tumors were established, mice were assigned to observation versus 4 doses of either OFA or RTX, and anti-tumor activity was measured by changes in tumor volume. Results: OFA induced higher CDC than RTX in all MCL cell lines tested (Mino: 65.9% vs. 0.5% ; Jeko 43.9% vs. 13.3% ; Rec-1 25.4% vs. 4.7% ; Z-138: 56.4% vs. 0.65%). No differences in ADCC were noted between OFA and RTX. In primary tumor cells, OFA and RTX demonstrated similar activity. CD20 levels were similar in all MCL cell lines tested. Of interest, CIP expression in MCL cell lines was higher when compared to other NHL cell lines, explaining differences observed between OFA and RTX. In vivo OFA was more effective in slowing tumor progression than RTX. Conclusions: Our data suggest OFA is more potent than RTX against MCL pre-clinical models. In addition and as expected, OFA exhibits potent CDC despite high expression of CIP. Our results support the evaluation of ofatumumab in future prospective clinical trials for patients with MCL.