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Biomedicines
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Animal Models of Human Pathology: Revision, Relevance and Refinements
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Animal Models of Human Pathology: Revision, Relevance and Refinements

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 98460

Special Issue Editor

Dr. Martina Perše

E-Mail Website
Guest Editor
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Interests: challenges in animal model research; translation; unbiased reporting of animal model characteristics and results; ethical justification
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Use of animal models of human pathology is accepted on the assumption that it benefits humans. However, recent publications have shown that research on animals faces serious challenges. The increasing number of potential targets, molecular pathways or treatment strategies, which have been recognized as promising in animal models, have failed when translated into human trials. We have reached the point where the clinical relevance of animal models needs urgent clarification.

Multiple methodological problems in animal research have already been exposed, such as poor experimental design, inadequate use of fundamental statistical principles (i.e., randomization, blinding, inadequate power, inadequate sample size, pseudo-replication, etc.), and nontransparent reporting, which results in low scientific validity and irreproducibility of results. However, research on animal models also requires comprehensive knowledge about the model, as well as an understanding of the complex pathogenesis of diseases, which involves both local and systemic effects in the body. Every animal model has its own characteristics, advantages, and limitations. There are factors specific to the disease or animal model that can influence not only the severity of the disease but also underlying mechanisms, and, when these factors are not taken into account, research may result in the discovery of new targets and disease pathways that are of no scientific or clinical value. There are also animal-model-specific factors that can seriously affect the results and lead to false conclusions and failed translation. Although overall animal health and welfare issues—such as animal clinical state, morbidity, mortality, humane endpoints and humane interventions, whole body necropsy findings, sampling principles, pathohistological diagnosis—are of vital importance in the interpretation of the molecular mechanisms or treatment strategies in an organism, this information is usually lacking or rarely properly addressed in animal model studies.

The purpose of this Special issue is thus to promote submissions of high-quality papers of basic research using animal models to understand diseases and underlying mechanisms or to investigate new treatment strategies in various human diseases such as cancer, bowel diseases, kidney injury, Parkinson’s disease, etc. New approaches towards the use of animal models or refinements of particular animal models of human pathology are also welcome.

Dr. Martina Perše
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • animal models
  • biomarkers
  • human disease
  • pathology
  • translation
  • mechanisms
  • nephrology
  • gastroenterology
  • urology
  • neuroscience
  • cancer

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Published Papers (23 papers)

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17 pages, 3603 KiB  
Article
Towards Standardisation of a Diffuse Midline Glioma Patient-Derived Xenograft Mouse Model Based on Suspension Matrices for Preclinical Research
by Elvin ’t Hart, John Bianco, Helena C. Besse, Lois A. Chin Joe Kie, Lesley Cornet, Kimberly L. Eikelenboom, Thijs J.M. van den Broek, Marc Derieppe, Yan Su, Eelco W. Hoving, Mario G. Ries and Dannis G. van Vuurden
Biomedicines 2023, 11(2), 527; https://doi.org/10.3390/biomedicines11020527 - 11 Feb 2023
Cited by 3 | Viewed by 3538
Abstract
Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack [...] Read more.
Diffuse midline glioma (DMG) is an aggressive brain tumour with high mortality and limited clinical therapeutic options. Although in vitro research has shown the effectiveness of medication, successful translation to the clinic remains elusive. A literature search highlighted the high variability and lack of standardisation in protocols applied for establishing the commonly used HSJD-DIPG-007 patient-derived xenograft (PDX) model, based on animal host, injection location, number of cells inoculated, volume, and suspension matrices. This study evaluated the HSJD-DIPG-007 PDX model with respect to its ability to mimic human disease progression for therapeutic testing in vivo. The mice received intracranial injections of HSJD-DIPG-007 cells suspended in either PBS or Matrigel. Survival, tumour growth, and metastases were assessed to evaluate differences in the suspension matrix used. After cell implantation, no severe side effects were observed. Additionally, no differences were detected in terms of survival or tumour growth between the two suspension groups. We observed delayed metastases in the Matrigel group, with a significant difference compared to mice with PBS-suspended cells. In conclusion, using Matrigel as a suspension matrix is a reliable method for establishing a DMG PDX mouse model, with delayed metastases formation and is a step forward to obtaining a standardised in vivo PDX model. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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21 pages, 2020 KiB  
Article
Molecular Abnormalities in BTBR Mice and Their Relevance to Schizophrenia and Autism Spectrum Disorders: An Overview of Transcriptomic and Proteomic Studies
by Polina Kisaretova, Anton Tsybko, Natalia Bondar and Vasiliy Reshetnikov
Biomedicines 2023, 11(2), 289; https://doi.org/10.3390/biomedicines11020289 - 20 Jan 2023
Cited by 7 | Viewed by 3602
Abstract
Animal models of psychopathologies are of exceptional interest for neurobiologists because these models allow us to clarify molecular mechanisms underlying the pathologies. One such model is the inbred BTBR strain of mice, which is characterized by behavioral, neuroanatomical, and physiological hallmarks of schizophrenia [...] Read more.
Animal models of psychopathologies are of exceptional interest for neurobiologists because these models allow us to clarify molecular mechanisms underlying the pathologies. One such model is the inbred BTBR strain of mice, which is characterized by behavioral, neuroanatomical, and physiological hallmarks of schizophrenia (SCZ) and autism spectrum disorders (ASDs). Despite the active use of BTBR mice as a model object, the understanding of the molecular features of this strain that cause the observed behavioral phenotype remains insufficient. Here, we analyzed recently published data from independent transcriptomic and proteomic studies on hippocampal and corticostriatal samples from BTBR mice to search for the most consistent aberrations in gene or protein expression. Next, we compared reproducible molecular signatures of BTBR mice with data on postmortem samples from ASD and SCZ patients. Taken together, these data helped us to elucidate brain-region-specific molecular abnormalities in BTBR mice as well as their relevance to the anomalies seen in ASDs or SCZ in humans. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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11 pages, 1627 KiB  
Article
Development and Characterization of a Subcutaneous Implant-Related Infection Model in Mice to Test Novel Antimicrobial Treatment Strategies
by Charlotte Wittmann, Niels Vanvelk, Anton E. Fürst, T. Fintan Moriarty and Stephan Zeiter
Biomedicines 2023, 11(1), 40; https://doi.org/10.3390/biomedicines11010040 - 24 Dec 2022
Cited by 3 | Viewed by 2230
Abstract
Orthopedic-device-related infection is one of the most severe complications in orthopedic surgery. To reduce the associated morbidity and healthcare costs, new prevention and treatment modalities are continuously under development. Preclinical in vivo models serve as a control point prior to clinical implementation. This [...] Read more.
Orthopedic-device-related infection is one of the most severe complications in orthopedic surgery. To reduce the associated morbidity and healthcare costs, new prevention and treatment modalities are continuously under development. Preclinical in vivo models serve as a control point prior to clinical implementation. This study presents a mouse model of subcutaneously implanted titanium discs, infected with Staphylococcus aureus, to fill a gap in the early-stage testing of antimicrobial biomaterials. Firstly, three different inocula were administered either pre-adhered to the implant or pipetted on top of it following implantation to test their ability to reliably create an infection. Secondly, the efficacy of low-dose (25 mg/kg) and high-dose (250 mg/kg) cefazolin administered systemically in infection prevention was assessed. Lastly, titanium implants were replaced by antibiotic-loaded bone cement (ALBC) discs to investigate the efficacy of local antibiotics in infection prevention. The efficacy in infection prevention of the low-dose perioperative antibiotic prophylaxis (PAP) depended on both the inoculum and inoculation method. Bacterial counts were significantly lower in animals receiving the high dose of PAP. ALBC discs with or without the additional PAP proved highly effective in infection prevention and provide a suitable positive control to test other prevention strategies. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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16 pages, 1931 KiB  
Article
Gabapentin Increases Intra-Epidermal and Peptidergic Nerve Fibers Density and Alleviates Allodynia and Thermal Hyperalgesia in a Mouse Model of Acute Taxol-Induced Peripheral Neuropathy
by Michal Klazas, Majdi Saleem Naamneh, Wenhua Zheng and Philip Lazarovici
Biomedicines 2022, 10(12), 3190; https://doi.org/10.3390/biomedicines10123190 - 8 Dec 2022
Cited by 3 | Viewed by 2501
Abstract
The clinical pathology of Taxol-induced peripheral neuropathy (TIPN), characterized by loss of sensory sensitivity and pain, is mirrored in a preclinical pharmacological mice model in which Gabapentin, produced anti-thermal hyperalgesia and anti-allodynia effects. The study aimed to investigate the hypothesis that gabapentin may [...] Read more.
The clinical pathology of Taxol-induced peripheral neuropathy (TIPN), characterized by loss of sensory sensitivity and pain, is mirrored in a preclinical pharmacological mice model in which Gabapentin, produced anti-thermal hyperalgesia and anti-allodynia effects. The study aimed to investigate the hypothesis that gabapentin may protect against Taxol-induced neuropathic pain in association with an effect on intra-epidermal nerve fibers density in the TIPN mice model. A TIPN study schedule was induced in mice by daily injection of Taxol during the first week of the experiment. Gabapentin therapy was performed during the 2nd and 3rd weeks. The neuropathic pain was evaluated during the whole experiment by the Von Frey, tail flick, and hot plate tests. Intra-epidermal nerve fibers (IENF) density in skin biopsies was measured at the end of the experiment by immunohistochemistry of ubiquitin carboxyl-terminal hydrolase PGP9.5 pan-neuronal and calcitonin gene-related (CGRP) peptides-I/II- peptidergic markers. Taxol-induced neuropathy was expressed by 80% and 73% reduction in the paw density of IENFs and CGPR, and gabapentin treatment corrected by 83% and 46% this reduction, respectively. Gabapentin-induced increase in the IENF and CGRP nerve fibers density, thus proposing these evaluations as an additional objective end-point tool in TIPN model studies using gabapentin as a reference compound. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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15 pages, 2836 KiB  
Article
A Novel Murine Multi-Hit Model of Perinatal Acute Diffuse White Matter Injury Recapitulates Major Features of Human Disease
by Patricia Renz, Andreina Schoeberlein, Valérie Haesler, Theoni Maragkou, Daniel Surbek and Amanda Brosius Lutz
Biomedicines 2022, 10(11), 2810; https://doi.org/10.3390/biomedicines10112810 - 4 Nov 2022
Cited by 2 | Viewed by 2295
Abstract
The selection of an appropriate animal model is key to the production of results with optimal relevance to human disease. Particularly in the case of perinatal brain injury, a dearth of affected human neonatal tissue available for research purposes increases the reliance on [...] Read more.
The selection of an appropriate animal model is key to the production of results with optimal relevance to human disease. Particularly in the case of perinatal brain injury, a dearth of affected human neonatal tissue available for research purposes increases the reliance on animal models for insight into disease mechanisms. Improvements in obstetric and neonatal care in the past 20 years have caused the pathologic hallmarks of perinatal white matter injury (WMI) to evolve away from cystic necrotic lesions and toward diffuse regions of reactive gliosis and persistent myelin disruption. Therefore, updated animal models are needed that recapitulate the key features of contemporary disease. Here, we report a murine model of acute diffuse perinatal WMI induced through a two-hit inflammatory–hypoxic injury paradigm. Consistent with diffuse human perinatal white matter injury (dWMI), our model did not show the formation of cystic lesions. Corresponding to cellular outcomes of dWMI, our injury protocol produced reactive microgliosis and astrogliosis, disrupted oligodendrocyte maturation, and disrupted myelination.. Functionally, we observed sensorimotor and cognitive deficits in affected mice. In conclusion, we report a novel murine model of dWMI that induces a pattern of brain injury mirroring multiple key aspects of the contemporary human clinical disease scenario. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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15 pages, 3624 KiB  
Article
Model of Acute Liver Failure in an Isolated Perfused Porcine Liver—Challenges and Lessons Learned
by Joshua Hefler, Sanaz Hatami, Aducio Thiesen, Carly Olafson, Kiarra Durand, Jason Acker, Constantine J. Karvellas, David L. Bigam, Darren H. Freed and Andrew Mark James Shapiro
Biomedicines 2022, 10(10), 2496; https://doi.org/10.3390/biomedicines10102496 - 6 Oct 2022
Cited by 2 | Viewed by 2133
Abstract
Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most [...] Read more.
Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most closely represent human disease, can be logistically and technically cumbersome, expensive and pose ethical challenges. The development of isolated organ perfusion technologies, originally intended for preservation before transplantation, offers a new platform for experimental models of liver disease, such as ALF. In this study, female domestic swine underwent hepatectomy, followed by perfusion of the isolated liver on a normothermic machine perfusion device. Five control livers were perfused for 24 h at 37 °C, while receiving supplemental oxygen and nutrition. Six livers received toxic doses of acetaminophen given over 12 h, titrated to methemoglobin levels. Perfusate was sampled every 4 h for measurement of biochemical markers of injury (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT]). Liver biopsies were taken at the beginning, middle, and end of perfusion for histological assessment. Acetaminophen-treated livers received a median dose of 8.93 g (8.21–9.75 g) of acetaminophen, achieving a peak acetaminophen level of 3780 µmol/L (3189–3913 µmol/L). Peak values of ALT (76 vs. 105 U/L; p = 0.429) and AST (3576 vs. 4712 U/L; p = 0.429) were not significantly different between groups. However, by the end of perfusion, histology scores were significantly worse in the acetaminophen treated group (p = 0.016). All acetaminophen treated livers developed significant methemoglobinemia, with a peak methemoglobin level of 19.3%, compared to 2.0% for control livers (p = 0.004). The development of a model of ALF in the ex vivo setting was confounded by the development of toxic methemoglobinemia. Further attempts using alternative agents or dosing strategies may be warranted to explore this setting as a model of liver disease. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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23 pages, 5297 KiB  
Article
Dexamethasone-Induced Adipose Tissue Redistribution and Metabolic Changes: Is Gene Expression the Main Factor? An Animal Model of Chronic Hypercortisolism
by Flaviane de Fatima Silva, Ayumi Cristina Medeiros Komino, Sandra Andreotti, Gabriela Boltes Reis, Rennan Oliveira Caminhotto, Richardt Gama Landgraf, Gabriel Orefice de Souza, Rogerio Antonio Laurato Sertié, Sheila Collins, Jose Donato, Jr. and Fabio Bessa Lima
Biomedicines 2022, 10(9), 2328; https://doi.org/10.3390/biomedicines10092328 - 19 Sep 2022
Cited by 6 | Viewed by 2684
Abstract
Chronic hypercortisolism has been associated with the development of several metabolic alterations, mostly caused by the effects of chronic glucocorticoid (GC) exposure over gene expression. The metabolic changes can be partially explained by the GC actions on different adipose tissues (ATs), leading to [...] Read more.
Chronic hypercortisolism has been associated with the development of several metabolic alterations, mostly caused by the effects of chronic glucocorticoid (GC) exposure over gene expression. The metabolic changes can be partially explained by the GC actions on different adipose tissues (ATs), leading to central obesity. In this regard, we aimed to characterize an experimental model of iatrogenic hypercortisolism in rats with significant AT redistribution. Male Wistar rats were distributed into control (CT) and GC-treated, which received dexamethasone sodium phosphate (0.5 mg/kg/day) by an osmotic minipump, for 4 weeks. GC-treated rats reproduced several characteristics observed in human hypercortisolism/Cushing’s syndrome, such as HPA axis inhibition, glucose intolerance, insulin resistance, dyslipidemia, hepatic lipid accumulation, and AT redistribution. There was an increase in the mesenteric (meWAT), perirenal (prWAT), and interscapular brown (BAT) ATs mass, but a reduction of the retroperitoneal (rpWAT) mass compared to CT rats. Overexpressed lipolytic and lipogenic gene profiles were observed in white adipose tissue (WAT) of GC rats as BAT dysfunction and whitening. The AT remodeling in response to GC excess showed more importance than the increase of AT mass per se, and it cannot be explained just by GC regulation of gene transcription. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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18 pages, 3410 KiB  
Article
Novel Endometrial Cancer Models Using Sensitive Metastasis Tracing for CXCR4-Targeted Therapy in Advanced Disease
by Esperanza Medina-Gutiérrez, María Virtudes Céspedes, Alberto Gallardo, Elisa Rioja-Blanco, Miquel Àngel Pavón, Laura Asensio-Puig, Lourdes Farré, Lorena Alba-Castellón, Ugutz Unzueta, Antonio Villaverde, Esther Vázquez, Isolda Casanova and Ramon Mangues
Biomedicines 2022, 10(7), 1680; https://doi.org/10.3390/biomedicines10071680 - 12 Jul 2022
Cited by 9 | Viewed by 2689
Abstract
Advanced endometrial cancer (EC) lacks therapy, thus, there is a need for novel treatment targets. CXCR4 overexpression is associated with a poor prognosis in several cancers, whereas its inhibition prevents metastases. We assessed CXCR4 expression in EC in women by using IHC. Orthotopic [...] Read more.
Advanced endometrial cancer (EC) lacks therapy, thus, there is a need for novel treatment targets. CXCR4 overexpression is associated with a poor prognosis in several cancers, whereas its inhibition prevents metastases. We assessed CXCR4 expression in EC in women by using IHC. Orthotopic models were generated with transendometrial implantation of CXCR4-transduced EC cells. After in vitro evaluation of the CXCR4-targeted T22-GFP-H6 nanocarrier, subcutaneous EC models were used to study its uptake in tumor and normal organs. Of the women, 91% overexpressed CXCR4, making them candidates for CXCR4-targeted therapies. Thus, we developed CXCR4+ EC mouse models to improve metastagenesis compared to current models and to use them to develop novel CXCR4-targeted therapies for unresponsive EC. It showed enhanced dissemination, especially in the lungs and liver, and displayed 100% metastasis penetrance at all clinically relevant sites with anti-hVimentin IHC, improving detection sensitivity. Regarding the CXCR4-targeted nanocarrier, 60% accumulated in the SC tumor; therefore, selectively targeting CXCR4+ cancer cells, without toxicity in non-tumor organs. Our CXCR4+ EC models will allow testing of novel CXCR4-targeted drugs and development of nanomedicines derived from T22-GFP-H6 to deliver drugs to CXCR4+ cells in advanced EC. This novel approach provides a therapeutic option for women with metastatic, high risk or recurrent EC that have a dismal prognosis and lack effective therapies. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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11 pages, 2703 KiB  
Article
Cardiac Cell Exposure to Electromagnetic Fields: Focus on Oxdative Stress and Apoptosis
by Ilenia Martinelli, Mathieu Cinato, Sokhna Keita, Dimitri Marsal, Valentin Antoszewski, Junwu Tao and Oksana Kunduzova
Biomedicines 2022, 10(5), 929; https://doi.org/10.3390/biomedicines10050929 - 19 Apr 2022
Cited by 8 | Viewed by 2379
Abstract
Exposure to electromagnetic fields (EMFs) is a sensitive research topic. Despite extensive research, to date there is no evidence to conclude that exposure to EMFs influences the cardiovascular system. In the present study, we examined whether 915 MHz EMF exposure affects myocardial antioxidative [...] Read more.
Exposure to electromagnetic fields (EMFs) is a sensitive research topic. Despite extensive research, to date there is no evidence to conclude that exposure to EMFs influences the cardiovascular system. In the present study, we examined whether 915 MHz EMF exposure affects myocardial antioxidative and apoptotic status in vitro and in vivo. No statistically significant difference in the apoptotic cell profile and antioxidant capacity was observed between controls and short-term EMF-exposed mouse cardiomyocytes and H9C2 cardiomyoblasts. Compared with sham-exposed controls, mice subjected to a 915 MHz EMF for 48 h and 72 h had no significant effect on structural tissue integrity and myocardial expression of apoptosis and antioxidant genes. Therefore, these results indicate that short-term exposure to EMF in cardiac cells and tissues did not translate into a significant effect on the myocardial antioxidant defense system and apoptotic cell death. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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14 pages, 1623 KiB  
Article
Taste-Driven Responsiveness to Fat and Sweet Stimuli in Mouse Models of Bariatric Surgery
by Aurélie Dastugue, Cédric Le May, Séverine Ledoux, Cindy Le Bourgot, Pascaline Delaby, Arnaud Bernard and Philippe Besnard
Biomedicines 2022, 10(4), 741; https://doi.org/10.3390/biomedicines10040741 - 22 Mar 2022
Cited by 2 | Viewed by 2385
Abstract
A preferential consumption of healthier foods, low in fat and sugar, is often reported after bariatric surgery, suggesting a switch of taste-guided food choices. To further explore this hypothesis in well-standardized conditions, analysis of licking behavior in response to oily and sweet solutions [...] Read more.
A preferential consumption of healthier foods, low in fat and sugar, is often reported after bariatric surgery, suggesting a switch of taste-guided food choices. To further explore this hypothesis in well-standardized conditions, analysis of licking behavior in response to oily and sweet solutions has been realized in rats that have undergone a Roux-en-Y bypass (RYGB). Unfortunately, these studies have produced conflicting data mainly due to methodological differences. Paradoxically, whereas the vertical sleeve gastrectomy (VSG) becomes the most commonly performed bariatric surgery worldwide and is easier to perform and standardize in small animals, its putative impacts on the orosensory perception of energy-dense nutrients remains unknown. Using brief-access licking tests in VSG or RYGB mice, we found that (i) VSG induces a significant reduction in the fat mass in diet-induced obese (DIO) mice, (ii) VSG partially corrects the licking responses to lipid and sucrose stimuli which are degraded in sham-operated DIO mice, (iii) VSG improves the willingness to lick oily and sucrose solutions in DIO mice and (iv) RYGB leads to close outcomes. Altogether, these data strongly suggest that VSG, as RYGB, can counteract the deleterious effect of obesity on the orosensory perception of energy-dense nutrients in mice. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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14 pages, 3546 KiB  
Article
Early-Onset Glaucoma in egl1 Mice Homozygous for Pitx2 Mutation
by Bindu Kodati, Shawn A. Merchant, J. Cameron Millar and Yang Liu
Biomedicines 2022, 10(3), 516; https://doi.org/10.3390/biomedicines10030516 - 22 Feb 2022
Cited by 1 | Viewed by 2248
Abstract
Mutations in PITX2 cause Axenfeld–Rieger syndrome, with congenital glaucoma as an ocular feature. The egl1 mouse strain carries a chemically induced Pitx2 mutation and develops early-onset glaucoma. In this study, we characterized the glaucomatous features in egl1 mice. The eyes of egl1 and [...] Read more.
Mutations in PITX2 cause Axenfeld–Rieger syndrome, with congenital glaucoma as an ocular feature. The egl1 mouse strain carries a chemically induced Pitx2 mutation and develops early-onset glaucoma. In this study, we characterized the glaucomatous features in egl1 mice. The eyes of egl1 and C57BL/6J control mice were assessed by slit lamp examination, total aqueous humor outflow facility, intraocular pressure (IOP) measurement, pattern electroretinography (PERG) recording, and histologic and immunohistochemistry assessment beginning at 3 weeks and up to 12 months of age. The egl1 mice developed elevated IOP as early as 4 weeks old. The IOP elevation was variable and asymmetric within and between the animals. The aqueous humor outflow facility was significantly reduced in 12-month-old animals. PERG detected a decreased response at 2 weeks after the development of IOP elevation. Retinal ganglion cell (RGC) loss was detected after 8 weeks of IOP elevation. Slit lamp and histologic evaluation revealed corneal opacity, iridocorneal adhesions (anterior synechiae), and ciliary body atrophy in egl1 mice. Immunohistochemistry assessment demonstrated glial cell activation and RGC axonal injury in response to IOP elevation. These results show that the eyes of egl1 mice exhibit anterior segment dysgenesis and early-onset glaucoma. The egl1 mouse strain may represent a useful model for the study of congenital glaucoma. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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18 pages, 2157 KiB  
Article
Low-Dose Metformin as a Monotherapy Does Not Reduce Non-Small-Cell Lung Cancer Tumor Burden in Mice
by Nicole L. Stott Bond, Didier Dréau, Ian Marriott, Jeanette M. Bennett, Michael J. Turner, Susan T. Arthur and Joseph S. Marino
Biomedicines 2021, 9(11), 1685; https://doi.org/10.3390/biomedicines9111685 - 14 Nov 2021
Cited by 1 | Viewed by 2711
Abstract
Non-small-cell lung cancer (NSCLC) makes up 80–85% of lung cancer diagnoses. Lung cancer patients undergo surgical procedures, chemotherapy, and/or radiation. Chemotherapy and radiation can induce deleterious systemic side effects, particularly within skeletal muscle. To determine whether metformin reduces NSCLC tumor burden while maintaining [...] Read more.
Non-small-cell lung cancer (NSCLC) makes up 80–85% of lung cancer diagnoses. Lung cancer patients undergo surgical procedures, chemotherapy, and/or radiation. Chemotherapy and radiation can induce deleterious systemic side effects, particularly within skeletal muscle. To determine whether metformin reduces NSCLC tumor burden while maintaining skeletal muscle health, C57BL/6J mice were injected with Lewis lung cancer (LL/2), containing a bioluminescent reporter for in vivo tracking, into the left lung. Control and metformin (250 mg/kg) groups received treatments twice weekly. Skeletal muscle was analyzed for changes in genes and proteins related to inflammation, muscle mass, and metabolism. The LL/2 model effectively mimics lung cancer growth and tumor burden. The in vivo data indicate that metformin as administered was not associated with significant improvement in tumor burden in this immunocompetent NSCLC model. Additionally, metformin was not associated with significant changes in key tumor cell division and inflammation markers, or improved skeletal muscle health. Metformin treatment, while exhibiting anti-neoplastic characteristics in many cancers, appears not to be an appropriate monotherapy for NSCLC tumor growth in vivo. Future studies should pursue co-treatment modalities, with metformin as a potentially supportive drug rather than a monotherapy to mitigate cancer progression. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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9 pages, 2681 KiB  
Article
Carollia perspicillata: A Small Bat with Tremendous Translational Potential for Studies of Brain Aging and Neurodegeneration
by Mark Stewart, Timothy Morello, Richard Kollmar and Rena Orman
Biomedicines 2021, 9(10), 1454; https://doi.org/10.3390/biomedicines9101454 - 13 Oct 2021
Cited by 4 | Viewed by 2672
Abstract
As the average human lifespan lengthens, the impact of neurodegenerative disease increases, both on the individual suffering neurodegeneration and on the community that supports those individuals. Studies aimed at understanding the mechanisms of neurodegeneration have relied heavily on observational studies of humans and [...] Read more.
As the average human lifespan lengthens, the impact of neurodegenerative disease increases, both on the individual suffering neurodegeneration and on the community that supports those individuals. Studies aimed at understanding the mechanisms of neurodegeneration have relied heavily on observational studies of humans and experimental studies in animals, such as mice, in which aspects of brain structure and function can be manipulated to target mechanistic steps. An animal model whose brain is structurally closer to the human brain, that lives much longer than rodents, and whose husbandry is practical may be valuable for mechanistic studies that cannot readily be conducted in rodents. To demonstrate that the long-lived Seba’s short-tailed fruit bat, Carollia perspicillata, may fit this role, we used immunohistochemical labeling for NeuN and three calcium-binding proteins, calretinin, parvalbumin, and calbindin, to define hippocampal formation anatomy. Our findings demonstrate patterns of principal neuron organization that resemble primate and human hippocampal formation and patterns of calcium-binding protein distribution that help to define subregional boundaries. Importantly, we present evidence for a clear prosubiculum in the bat brain that resembles primate prosubiculum. Based on the similarities between bat and human hippocampal formation anatomy, we suggest that Carollia has unique advantages for the study of brain aging and neurodegeneration. A captive colony of Carollia allows age tracking, diet and environment control, pharmacological manipulation, and access to behavioral, physiological, anatomical, and molecular evaluation. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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20 pages, 3251 KiB  
Article
Sex-Related Motor Deficits in the Tau-P301L Mouse Model
by Luana Cristina Camargo, Dominik Honold, Robert Bauer, N. Jon Shah, Karl-Josef Langen, Dieter Willbold, Janine Kutzsche, Antje Willuweit and Sarah Schemmert
Biomedicines 2021, 9(9), 1160; https://doi.org/10.3390/biomedicines9091160 - 4 Sep 2021
Cited by 5 | Viewed by 2645
Abstract
The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes [...] Read more.
The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes are influenced by the sex. For this purpose, we performed an in-depth characterization of the behavioral alterations in the transgenic Tau-P301L mouse model. Sex-matched wild type and homozygous Tau-P301L mice were tested in a battery of behavioral tests at different ages. Tau-P301L male mice showed olfactory and motor deficits as well as increased Tau pathology, which was not observed in Tau-P301L female mice. Both Tau-P301L male and female mice had phenotypic alterations in the SHIRPA test battery and cognitive deficits in the novel object recognition test. This study demonstrated that Tau-P301L mice have phenotypic alterations, which are in line with the histological changes and with a sex-dependent performance in those tests. Summarized, the Tau-P301L mouse model shows phenotypic alterations due to the presence of neurofibrillary tangles in the brain. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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21 pages, 2372 KiB  
Article
Local Experimental Intracerebral Hemorrhage in Rats
by Ekaterina Vasilevskaya, Aleksandr Makarenko, Galina Tolmacheva, Irina Chernukha, Anastasiya Kibitkina and Liliya Fedulova
Biomedicines 2021, 9(6), 585; https://doi.org/10.3390/biomedicines9060585 - 21 May 2021
Cited by 1 | Viewed by 2918
Abstract
(1) Background: Hemorrhagic stroke is a lethal disease, accounting for 15% of all stroke cases. However, there are very few models of stroke with a hemorrhagic etiology. Research work is devoted to studying the development of cerebrovascular disorders in rats with an intracerebral [...] Read more.
(1) Background: Hemorrhagic stroke is a lethal disease, accounting for 15% of all stroke cases. However, there are very few models of stroke with a hemorrhagic etiology. Research work is devoted to studying the development of cerebrovascular disorders in rats with an intracerebral hematoma model. The aim of this study was to conduct a comprehensive short-term study, including neurological tests, biochemical blood tests, and histomorphological studies of brain structures. (2) Methods: The model was reproduced surgically by traumatizing the brain in the capsula interna area and then injecting autologous blood. Neurological deficit was assessed according to the McGrow stroke-index scale, motor activity, orientation–exploratory behavior, emotionality, and motor functions. On Day 15, after the operation, hematological and biochemical blood tests as well as histological studies of the brain were performed. (3) Results: The overall lethality of the model was 43.7%. Acute intracerebral hematoma in rats causes marked disorders of motor activity and functional impairment, as well as inflammatory processes in the nervous tissue, which persist for at least 14 days. (4) Conclusions: This model reflects the situation observed in the clinic and reproduces the main diagnostic criteria for acute disorders of cerebral circulation. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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17 pages, 2271 KiB  
Article
Potential Mucosal Irritation Discrimination of Surface Disinfectants Employed against SARS-CoV-2 by Limacus flavus Slug Mucosal Irritation Assay
by Marco Alfio Cutuli, Antonio Guarnieri, Laura Pietrangelo, Irene Magnifico, Noemi Venditti, Laura Recchia, Katia Mangano, Ferdinando Nicoletti, Roberto Di Marco and Giulio Petronio Petronio
Biomedicines 2021, 9(4), 424; https://doi.org/10.3390/biomedicines9040424 - 14 Apr 2021
Cited by 5 | Viewed by 3275
Abstract
Preventive measures have proven to be the most effective strategy to counteract the spread of the SARS-CoV-2 virus. Among these, disinfection is strongly suggested by international health organizations’ official guidelines. As a consequence, the increase of disinfectants handling is going to expose people [...] Read more.
Preventive measures have proven to be the most effective strategy to counteract the spread of the SARS-CoV-2 virus. Among these, disinfection is strongly suggested by international health organizations’ official guidelines. As a consequence, the increase of disinfectants handling is going to expose people to the risk of eyes, mouth, nose, and mucous membranes accidental irritation. To assess mucosal irritation, previous studies employed the snail Arion lusitanicus as the mucosal model in Slug Mucosal Irritation (SMI) assay. The obtained results confirmed snails as a suitable experimental model for their anatomical characteristics superimposable to the human mucosae and the different easily observed readouts. Another terrestrial gastropod, Limacus flavus, also known as “ Yellow slug “, due to its larger size and greater longevity, has already been proposed as an SMI assay alternative model. In this study, for the first time, in addition to the standard parameters recorded in the SMI test, the production of yellow pigment in response to irritants, unique to the snail L. flavus, was evaluated. Our results showed that this species would be a promising model for mucosal irritation studies. The study conducted testing among all those chemical solutions most commonly recommended against the SARS-CoV-2 virus. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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26 pages, 4193 KiB  
Article
Probing Skin Barrier Recovery on Molecular Level Following Acute Wounds: An In Vivo/Ex Vivo Study on Pigs
by Enamul Haque Mojumdar, Lone Bruhn Madsen, Henri Hansson, Ida Taavoniku, Klaus Kristensen, Christina Persson, Anna Karin Morén, Rajmund Mokso, Artur Schmidtchen, Tautgirdas Ruzgas and Johan Engblom
Biomedicines 2021, 9(4), 360; https://doi.org/10.3390/biomedicines9040360 - 31 Mar 2021
Cited by 6 | Viewed by 5844
Abstract
Proper skin barrier function is paramount for our survival, and, suffering injury, there is an acute need to restore the lost barrier and prevent development of a chronic wound. We hypothesize that rapid wound closure is more important than immediate perfection of the [...] Read more.
Proper skin barrier function is paramount for our survival, and, suffering injury, there is an acute need to restore the lost barrier and prevent development of a chronic wound. We hypothesize that rapid wound closure is more important than immediate perfection of the barrier, whereas specific treatment may facilitate perfection. The aim of the current project was therefore to evaluate the quality of restored tissue down to the molecular level. We used Göttingen minipigs with a multi-technique approach correlating wound healing progression in vivo over three weeks, monitored by classical methods (e.g., histology, trans-epidermal water loss (TEWL), pH) and subsequent physicochemical characterization of barrier recovery (i.e., small and wide-angle X-ray diffraction (SWAXD), polarization transfer solid-state NMR (PTssNMR), dynamic vapor sorption (DVS), Fourier transform infrared (FTIR)), providing a unique insight into molecular aspects of healing. We conclude that although acute wounds sealed within two weeks as expected, molecular investigation of stratum corneum (SC) revealed a poorly developed keratin organization and deviations in lipid lamellae formation. A higher lipid fluidity was also observed in regenerated tissue. This may have been due to incomplete lipid conversion during barrier recovery as glycosphingolipids, normally not present in SC, were indicated by infrared FTIR spectroscopy. Evidently, a molecular approach to skin barrier recovery could be a valuable tool in future development of products targeting wound healing. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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Review

Jump to: Research, Other

25 pages, 2545 KiB  
Review
Pathophysiological Studies of Monoaminergic Neurotransmission Systems in Valproic Acid-Induced Model of Autism Spectrum Disorder
by Hsiao-Ying Kuo and Fu-Chin Liu
Biomedicines 2022, 10(3), 560; https://doi.org/10.3390/biomedicines10030560 - 27 Feb 2022
Cited by 18 | Viewed by 6146
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. The core syndromes of ASD are deficits in social communication and self-restricted interests and repetitive behaviors. Social communication relies on the proper integration of sensory and motor functions, which is tightly interwoven [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. The core syndromes of ASD are deficits in social communication and self-restricted interests and repetitive behaviors. Social communication relies on the proper integration of sensory and motor functions, which is tightly interwoven with the limbic function of reward, motivation, and emotion in the brain. Monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, are key players in the modulation of neuronal activity. Owing to their broad distribution, the monoamine neurotransmitter systems are well suited to modulate social communication by coordinating sensory, motor, and limbic systems in different brain regions. The complex and diverse functions of monoamine neurotransmission thus render themselves as primary targets of pathophysiological investigation of the etiology of ASD. Clinical studies have reported that children with maternal exposure to valproic acid (VPA) have an increased risk of developing ASD. Extensive animal studies have confirmed that maternal treatments of VPA include ASD-like phenotypes, including impaired social communication and repetitive behavior. Here, given that ASD is a neurodevelopmental disorder, we begin with an overview of the neural development of monoaminergic systems with their neurochemical properties in the brain. We then review and discuss the evidence of human clinical and animal model studies of ASD with a focus on the VPA-induced pathophysiology of monoamine neurotransmitter systems. We also review the potential interactions of microbiota and monoamine neurotransmitter systems in ASD pathophysiology. Widespread and complex changes in monoamine neurotransmitters are detected in the brains of human patients with ASD and validated in animal models. ASD animal models are not only essential to the characterization of pathogenic mechanisms, but also provide a preclinical platform for developing therapeutic approaches to ASD. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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34 pages, 17324 KiB  
Review
Pathophysiology of Perinatal Asphyxia in Humans and Animal Models
by Daniel Mota-Rojas, Dina Villanueva-García, Alfonso Solimano, Ramon Muns, Daniel Ibarra-Ríos and Andrea Mota-Reyes
Biomedicines 2022, 10(2), 347; https://doi.org/10.3390/biomedicines10020347 - 1 Feb 2022
Cited by 39 | Viewed by 14879
Abstract
Perinatal asphyxia is caused by lack of oxygen delivery (hypoxia) to end organs due to an hypoxemic or ischemic insult occurring in temporal proximity to labor (peripartum) or delivery (intrapartum). Hypoxic–ischemic encephalopathy is the clinical manifestation of hypoxic injury to the brain and [...] Read more.
Perinatal asphyxia is caused by lack of oxygen delivery (hypoxia) to end organs due to an hypoxemic or ischemic insult occurring in temporal proximity to labor (peripartum) or delivery (intrapartum). Hypoxic–ischemic encephalopathy is the clinical manifestation of hypoxic injury to the brain and is usually graded as mild, moderate, or severe. The search for useful biomarkers to precisely predict the severity of lesions in perinatal asphyxia and hypoxic–ischemic encephalopathy (HIE) is a field of increasing interest. As pathophysiology is not fully comprehended, the gold standard for treatment remains an active area of research. Hypothermia has proven to be an effective neuroprotective strategy and has been implemented in clinical routine. Current studies are exploring various add-on therapies, including erythropoietin, xenon, topiramate, melatonin, and stem cells. This review aims to perform an updated integration of the pathophysiological processes after perinatal asphyxia in humans and animal models to allow us to answer some questions and provide an interim update on progress in this field. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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28 pages, 4323 KiB  
Review
Cisplatin Mouse Models: Treatment, Toxicity and Translatability
by Martina Perše
Biomedicines 2021, 9(10), 1406; https://doi.org/10.3390/biomedicines9101406 - 7 Oct 2021
Cited by 71 | Viewed by 7350
Abstract
Cisplatin is one of the most widely used chemotherapeutic drugs in the treatment of a wide range of pediatric and adult malignances. However, it has various side effects which limit its use. Cisplatin mouse models are widely used in studies investigating cisplatin therapeutic [...] Read more.
Cisplatin is one of the most widely used chemotherapeutic drugs in the treatment of a wide range of pediatric and adult malignances. However, it has various side effects which limit its use. Cisplatin mouse models are widely used in studies investigating cisplatin therapeutic and toxic effects. However, despite numerous promising results, no significant improvement in treatment outcome has been achieved in humans. There are many drawbacks in the currently used cisplatin protocols in mice. In the paper, the most characterized cisplatin protocols are summarized together with weaknesses that need to be improved in future studies, including hydration and supportive care. As demonstrated, mice respond to cisplatin treatment in similar ways to humans. The paper thus aims to illustrate the complexity of cisplatin side effects (nephrotoxicity, gastrointestinal toxicity, neurotoxicity, ototoxicity and myelotoxicity) and the interconnectedness and interdependence of pathomechanisms among tissues and organs in a dose- and time-dependent manner. The paper offers knowledge that can help design future studies more efficiently and interpret study outcomes more critically. If we want to understand molecular mechanisms and find therapeutic agents that would have a potential benefit in clinics, we need to change our approach and start to treat animals as patients and not as tools. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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10 pages, 258 KiB  
Review
Relevance and Recommendations for the Application of Cardioplegic Solutions in Cardiopulmonary Bypass Surgery in Pigs
by Anna Glöckner, Susann Ossmann, Andre Ginther, Jagdip Kang, Michael A. Borger, Alexandro Hoyer and Maja-Theresa Dieterlen
Biomedicines 2021, 9(9), 1279; https://doi.org/10.3390/biomedicines9091279 - 21 Sep 2021
Cited by 3 | Viewed by 2311
Abstract
Cardioplegic solutions play a major role in cardiac surgery due to the fact that they create a silent operating field and protect the myocardium against ischemia and reperfusion injury. For studies on cardioplegic solutions, it is important to compare their effects and to [...] Read more.
Cardioplegic solutions play a major role in cardiac surgery due to the fact that they create a silent operating field and protect the myocardium against ischemia and reperfusion injury. For studies on cardioplegic solutions, it is important to compare their effects and to have a valid platform for preclinical testing of new cardioplegic solutions and their additives. Due to the strong anatomical and physiological cardiovascular similarities between pigs and humans, porcine models are suitable for investigating the effects of cardioplegic solutions. This review provides an overview of the results of the application of cardioplegic solutions in adult or pediatric pig models over the past 25 years. The advantages, disadvantages, limitations, and refinement strategies of these models are discussed. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
21 pages, 1361 KiB  
Review
Animal Models for DOHaD Research: Focus on Hypertension of Developmental Origins
by Chien-Ning Hsu and You-Lin Tain
Biomedicines 2021, 9(6), 623; https://doi.org/10.3390/biomedicines9060623 - 31 May 2021
Cited by 33 | Viewed by 5048
Abstract
Increasing evidence suggests that fetal programming through environmental exposure during a critical window of early life leads to long-term detrimental outcomes, by so-called developmental origins of health and disease (DOHaD). Hypertension can originate in early life. Animal models are essential for providing convincing [...] Read more.
Increasing evidence suggests that fetal programming through environmental exposure during a critical window of early life leads to long-term detrimental outcomes, by so-called developmental origins of health and disease (DOHaD). Hypertension can originate in early life. Animal models are essential for providing convincing evidence of a causal relationship between diverse early-life insults and the developmental programming of hypertension in later life. These insults include nutritional imbalances, maternal illnesses, exposure to environmental chemicals, and medication use. In addition to reviewing the various insults that contribute to hypertension of developmental origins, this review focuses on the benefits of animal models in addressing the underlying mechanisms by which early-life interventions can reprogram disease processes and prevent the development of hypertension. Our understanding of hypertension of developmental origins has been enhanced by each of these animal models, narrowing the knowledge gap between animal models and future clinical translation. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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Other

Jump to: Research, Review

23 pages, 1569 KiB  
Systematic Review
A Systematic Review of Therapeutic Approaches Used in Experimental Models of Interstitial Cystitis/Bladder Pain Syndrome
by Tadeja Kuret, Dominika Peskar, Andreja Erman and Peter Veranič
Biomedicines 2021, 9(8), 865; https://doi.org/10.3390/biomedicines9080865 - 22 Jul 2021
Cited by 17 | Viewed by 8949
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a multifactorial, chronic bladder disorder with limited therapeutic options currently available. The present review provides an extensive overview of therapeutic approaches used in in vitro, ex vivo, and in vivo experimental models of IC/BPS. Publications were identified [...] Read more.
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a multifactorial, chronic bladder disorder with limited therapeutic options currently available. The present review provides an extensive overview of therapeutic approaches used in in vitro, ex vivo, and in vivo experimental models of IC/BPS. Publications were identified by electronic search of three online databases. Data were extracted for study design, type of treatment, main findings, and outcome, as well as for methodological quality and the reporting of measures to avoid bias. A total of 100 full-text articles were included. The majority of identified articles evaluated therapeutic agents currently recommended to treat IC/BPS by the American Urological Association guidelines (21%) and therapeutic agents currently approved to treat other diseases (11%). More recently published articles assessed therapeutic approaches using stem cells (11%) and plant-derived agents (10%), while novel potential drug targets identified were proteinase-activated (6%) and purinergic (4%) receptors, transient receptor potential channels (3%), microRNAs (2%), and activation of the cannabinoid system (7%). Our results show that the reported methodological quality of animal studies could be substantially improved, and measures to avoid bias should be more consistently reported in order to increase the value of preclinical research in IC/BPS for potential translation to a clinical setting. Full article
(This article belongs to the Special Issue Animal Models of Human Pathology: Revision, Relevance and Refinements)
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