Topic Editors

Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada
Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Jeonbuk National University, Iksan 54596, Korea

Animal Model in Biomedical Research

Abstract submission deadline
closed (31 August 2021)
Manuscript submission deadline
closed (31 December 2021)
Viewed by
162555

Topic Information

Dear Colleagues,

Animals have long been used in biomedical reseach and contributed to finding solutions to biological and medical issues. Laboratory animal models have been developed for the study of human diseases; as a result, they have contributed to improving human health by helping scientists better understand disease physiopathology and thus more accurately identify molecular targets of drug treatment. Today, a variety of animal models are still being developed and are currently being utilized for research purposes in laboratories.

Therefore, this Topic will consider articles on all types of in vivo studies with animal models including genetics, behavioural, diseases models, and bioinformatics. Additionally, we also welcome submission of research focusing on the physiopathology of diseases, molecular mechanisms and actions of biologically active compounds in animal disease models.

Prof. Dr. Marc Ekker
Dr. Dong Kwon Yang
Topic Editors

Keywords

  • animal models
  • in vivo study
  • genetics
  • bioactive compounds
  • disease model
  • preclinical compounds testing

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomedicines
biomedicines
4.7 3.7 2013 15.4 Days CHF 2600
Pharmaceutics
pharmaceutics
5.4 6.9 2009 14.2 Days CHF 2900
Pharmaceuticals
pharmaceuticals
4.6 4.7 2004 14.6 Days CHF 2900
Cancers
cancers
5.2 7.4 2009 17.9 Days CHF 2900
Vaccines
vaccines
7.8 7.0 2013 19.2 Days CHF 2700

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Published Papers (63 papers)

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9 pages, 2674 KiB  
Article
Increased Production of Inflammatory Cytokines after Inoculation with Recombinant Zoster Vaccine in Mice
by Tetsuo Nakayama, Akihito Sawada and Takeshi Ito
Vaccines 2022, 10(8), 1339; https://doi.org/10.3390/vaccines10081339 - 18 Aug 2022
Cited by 3 | Viewed by 1685
Abstract
Increasing numbers of patients with zoster were reported recently, and recombinant zoster vaccine (Shingrix®) was licensed using the AS01B adjuvant system. Although it induces highly effective protection, a high incidence of local adverse events (regional pain, erythema, and swelling) has [...] Read more.
Increasing numbers of patients with zoster were reported recently, and recombinant zoster vaccine (Shingrix®) was licensed using the AS01B adjuvant system. Although it induces highly effective protection, a high incidence of local adverse events (regional pain, erythema, and swelling) has been reported with systemic reactions of fever, fatigue, and headache. To investigate the mechanism of local adverse events, cytokine profiles were investigated in mice injected with 0.1 mL of Shingrix®. Muscle tissue and serum samples were obtained on days 0, 1, 3, 5, and 7, and at 2 and 4 weeks after the first dose. The second dose was given 4 weeks after the first dose and samples were obtained on days 1, 3, 5, 7, and 14. IL-6 and G-CSF were detected in muscle tissues on day 1 of the first injection, decreased on day 3 and afterward, and enhanced production was demonstrated on day 1 of the second dose. In sera, the elevated levels of IL-6 were detected on day 1 of the first dose, and IL-10 was detected on day 1 with increased levels on day 3 of the first dose. IL-4 was detected in muscle tissue on day 1 of the second dose and IL-5 on day 1 of both the first and second doses. IFN-γ production was not enhanced in muscle tissue but increased in serum samples on day 1 of the first dose. These results in the mouse model indicate that the induction of inflammatory cytokines is related to the cause of adverse events in humans. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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19 pages, 3435 KiB  
Article
Transcriptomic Profiling of Gene Expression Associated with Granulosa Cell Tumor Development in a Mouse Model
by Nan Ni, Xin Fang, Destiny A. Mullens, James J. Cai, Ivan Ivanov, Laurent Bartholin and Qinglei Li
Cancers 2022, 14(9), 2184; https://doi.org/10.3390/cancers14092184 - 27 Apr 2022
Cited by 3 | Viewed by 2407
Abstract
Ovarian granulosa cell tumors (GCTs) are rare sex cord-stromal tumors, accounting for ~5% ovarian tumors. The etiology of GCTs remains poorly defined. Genetically engineered mouse models are potentially valuable for understanding the pathogenesis of GCTs. Mice harboring constitutively active TGFβ signaling (TGFBR1-CA) develop [...] Read more.
Ovarian granulosa cell tumors (GCTs) are rare sex cord-stromal tumors, accounting for ~5% ovarian tumors. The etiology of GCTs remains poorly defined. Genetically engineered mouse models are potentially valuable for understanding the pathogenesis of GCTs. Mice harboring constitutively active TGFβ signaling (TGFBR1-CA) develop ovarian GCTs that phenocopy several hormonal and molecular characteristics of human GCTs. To determine molecular alterations in the ovary upon TGFβ signaling activation, we performed transcriptomic profiling of gene expression associated with GCT development using ovaries from 1-month-old TGFBR1-CA mice and age-matched controls. RNA-sequencing and bioinformatics analysis coupled with the validation of select target genes revealed dysregulations of multiple cellular events and signaling molecules/pathways. The differentially expressed genes are enriched not only for known GCT-related pathways and tumorigenic events but also for signaling events potentially mediated by neuroactive ligand-receptor interaction, relaxin signaling, insulin signaling, and complements in TGFBR1-CA ovaries. Additionally, a comparative analysis of our data in mice with genes dysregulated in human GCTs or granulosa cells overexpressing a mutant FOXL2, the genetic hallmark of adult GCTs, identified some common genes altered in both conditions. In summary, this study has revealed the molecular signature of ovarian GCTs in a mouse model that harbors the constitutive activation of TGFBR1. The findings may be further exploited to understand the pathogenesis of a class of poorly defined ovarian tumors. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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2 pages, 966 KiB  
Correction
Correction: Alfaro-Arnedo et al. IGF1R as a Potential Pharmacological Target in Allergic Asthma. Biomedicines 2021, 9, 912
by Elvira Alfaro-Arnedo, Icíar P. López, Sergio Piñeiro-Hermida, Álvaro C. Ucero, Francisco J. González-Barcala, Francisco J. Salgado and José G. Pichel
Biomedicines 2022, 10(4), 733; https://doi.org/10.3390/biomedicines10040733 - 22 Mar 2022
Viewed by 1190
Abstract
In the original article [...] Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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11 pages, 689 KiB  
Article
Comparative Study of the Aftereffect of CO2 Inhalation or Tiletamine–Zolazepam–Xylazine Anesthesia on Laboratory Outbred Rats and Mice
by Oksana N. Khokhlova, Natalya A. Borozdina, Elena S. Sadovnikova, Irina A. Pakhomova, Pavel A. Rudenko, Yuliya V. Korolkova, Sergey A. Kozlov and Igor A. Dyachenko
Biomedicines 2022, 10(2), 512; https://doi.org/10.3390/biomedicines10020512 - 21 Feb 2022
Cited by 5 | Viewed by 2047
Abstract
CO2 inhalation is currently the most common method of euthanasia for laboratory rats and mice, and it is often used for further terminal blood sampling for clinical biochemical assays. Lately, this method has been criticized due to animal welfare issues associated with [...] Read more.
CO2 inhalation is currently the most common method of euthanasia for laboratory rats and mice, and it is often used for further terminal blood sampling for clinical biochemical assays. Lately, this method has been criticized due to animal welfare issues associated with some processes that develop after CO2 inhalation. The stress reaction and the value of the clinical laboratory parameters significantly depend on the used anesthetics, method, and the site of blood sampling. Especially in small rodents, an acute terminal state followed by a cascade of metabolic reactions that can affect the studied biochemical profile may develop and cause unnecessary suffering of animals. The aim of this study was to compare the stability of biochemical parameters of outbred Sprague Dawley rats and CD-1 mice serum collected after CO2 inhalation or the intramuscular injection of tiletamine–zolazepam–xylazine (TZX). The serum content of total protein and albumin, cholesterol, triglycerides, aspartate aminotransferase (AST), alanine aminotr ansferase (ALT), alkaline phosphatase (ALP), total bilirubin, and creatinine was decreased by the injection of TZX in comparison with CO2 inhalation. In addition, the levels of calcium, phosphates, chlorides and potassium were lowered by TZX vs. CO2 administration, while the level of sodium increased. Finally, the level of the majority of serum clinical biochemical parameters in rats and mice tend to be overestimated after CO2 inhalation, which may lead to masking the possible effect of anti-inflammatory drugs in animal tests. Injection anesthesia for small rodents with TZX is a more feasible method for terminal blood sampling, which also reduces the suffering of animals. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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13 pages, 3398 KiB  
Article
Myotendinous Junction: Exercise Protocols Can Positively Influence Their Development in Rats
by Jurandyr Pimentel Neto, Lara Caetano Rocha-Braga, Carolina dos Santos Jacob, André Neri Tomiate and Adriano Polican Ciena
Biomedicines 2022, 10(2), 480; https://doi.org/10.3390/biomedicines10020480 - 18 Feb 2022
Cited by 1 | Viewed by 1747
Abstract
The myotendinous junction (MTJ) is an interface that different stimuli alter their morphology. One of the main stimuli to promote alterations in the MTJ morphology is physical exercise. The present study aimed to investigate the morphology and molecular MTJ adaptations of biceps brachii [...] Read more.
The myotendinous junction (MTJ) is an interface that different stimuli alter their morphology. One of the main stimuli to promote alterations in the MTJ morphology is physical exercise. The present study aimed to investigate the morphology and molecular MTJ adaptations of biceps brachii muscle in adult Wistar rats submitted to different ladder-based protocols. Forty Wistar rats (90 days old) were divided into four groups: Sedentary (S), Climbing (C), Overload Climbing (OC), Climbing, and Overload Climbing (COC). The results of light microscopy demonstrated the cell and collagen tissue reorganization in the experimental groups. The sarcomeres lengths of different regions showed a particular development according to the specific protocols. The sarcoplasmic invaginations and evaginations demonstrated positive increases that promoted the myotendinous interface development. In the extracellular matrix, the structures presented an increase principally in the COC group. Finally, the immunofluorescence analysis showed the telocytes disposition adjacent to the MTJ region in all experimental groups, revealing their network organization. Thus, we concluded that the different protocols contributed to the morphological adaptations with beneficial effects in distinct ways of tissue and cellular development and can be used as a model for MTJ remodeling to future proteomic and genetic analysis. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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23 pages, 22399 KiB  
Review
The Evolution of Pharmacological Activities Bouea macrophylla Griffith In Vivo and In Vitro Study: A Review
by Intan Tsamrotul Fu’adah, Sri Adi Sumiwi and Gofarana Wilar
Pharmaceuticals 2022, 15(2), 238; https://doi.org/10.3390/ph15020238 - 16 Feb 2022
Cited by 6 | Viewed by 3675
Abstract
Bouea macrophylla Griffith (B. macrophylla) is one of the many herbal plants found in Asia, and its fruit is plum mango. This plant is rich in secondary metabolites, including flavonoids, tannins, polyphenolic compounds, and many others. Due to its bioactive components, plum [...] Read more.
Bouea macrophylla Griffith (B. macrophylla) is one of the many herbal plants found in Asia, and its fruit is plum mango. This plant is rich in secondary metabolites, including flavonoids, tannins, polyphenolic compounds, and many others. Due to its bioactive components, plum mango has powerful antioxidants that have therapeutic benefits for many common ailments, including cardiovascular disease, diabetes, and cancer. This review describes the evolution of plum mango’s phytochemical properties and pharmacological activities including in vitro and in vivo studies. The pharmacological activities of B. macrophylla Griffith reviewed in this article are antioxidant, anticancer, antihyperglycemic, antimicrobial, and antiphotoaging. Each of these pharmacological activities described and studied the possible cellular and molecular mechanisms of action. Interestingly, plum mango seeds show good pharmacological activity where the seed is the part of the plant that is a waste product. This can be an advantage because of its economic value as a herbal medicine. Overall, the findings described in this review aim to allow this plant to be explored and utilized more widely, especially as a new drug discovery. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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15 pages, 29395 KiB  
Article
Loss of atm in Zebrafish as a Model of Ataxia–Telangiectasia Syndrome
by Kehua Chen, Peng Wang, Jingrun Chen, Yiling Ying, Yi Chen, Eric Gilson, Yiming Lu and Jing Ye
Biomedicines 2022, 10(2), 392; https://doi.org/10.3390/biomedicines10020392 - 07 Feb 2022
Cited by 3 | Viewed by 2698
Abstract
Ataxia–telangiectasia mutated (ATM) is a key DNA damage signaling kinase that is mutated in humans with ataxia–telangiectasia (A-T) syndrome. This syndrome is characterized by neurodegeneration, immune abnormality, cancer predisposition, and premature aging. To better understand the function of ATM in vivo, [...] Read more.
Ataxia–telangiectasia mutated (ATM) is a key DNA damage signaling kinase that is mutated in humans with ataxia–telangiectasia (A-T) syndrome. This syndrome is characterized by neurodegeneration, immune abnormality, cancer predisposition, and premature aging. To better understand the function of ATM in vivo, we engineered a viable zebrafish model with a mutated atm gene. Zebrafish atm loss-of-function mutants show characteristic features of A-T-like motor disturbance, including coordination disorders, immunodeficiency, and tumorigenesis. The immunological disorder of atm homozygote fish is linked to the developmental blockade of hematopoiesis, which occurs at the adulthood stage and results in a decrease in infection defense but, with little effect on wound healing. Malignant neoplasms found in atm mutant fish were mainly nerve sheath tumors and myeloid leukemia, which rarely occur in A-T patients or Atm−/− mice. These results underscore the importance of atm during immune cell development. This zebrafish A-T model opens up a pathway to an improved understanding of the molecular basis of tumorigenesis in A-T and the cellular role of atm. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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13 pages, 2728 KiB  
Article
MALAT1 Fusions and Basal Cells Contribute to Primary Resistance against Androgen Receptor Inhibition in TRAMP Mice
by Maximilian Marhold, Simon Udovica, Thais Topakian, Peter Horak, Reinhard Horvat, Erwin Tomasich, Gerwin Heller and Michael Krainer
Cancers 2022, 14(3), 749; https://doi.org/10.3390/cancers14030749 - 31 Jan 2022
Cited by 2 | Viewed by 2431
Abstract
Targeting testosterone signaling through androgen deprivation therapy (ADT) or antiandrogen treatment is the standard of care for advanced prostate cancer (PCa). Although the large majority of patients initially respond to ADT and/or androgen receptor (AR) blockade, most patients suffering from advanced PCa will [...] Read more.
Targeting testosterone signaling through androgen deprivation therapy (ADT) or antiandrogen treatment is the standard of care for advanced prostate cancer (PCa). Although the large majority of patients initially respond to ADT and/or androgen receptor (AR) blockade, most patients suffering from advanced PCa will experience disease progression. We sought to investigate drivers of primary resistance against antiandrogen treatment in the TRAMP mouse model, an SV-40 t-antigen driven model exhibiting aggressive variants of prostate cancer, castration resistance, and neuroendocrine differentiation upon antihormonal treatment. We isolated primary tumor cell suspensions from adult male TRAMP mice and subjected them to organoid culture. Basal and non-basal cell populations were characterized by RNA sequencing, Western blotting, and quantitative real-time PCR. Furthermore, effects of androgen withdrawal and enzalutamide treatment were studied. Basal and luminal TRAMP cells exhibited distinct molecular signatures and gave rise to organoids with distinct phenotypes. TRAMP cells exhibited primary resistance against antiandrogen treatment. This was more pronounced in basal cell-derived TRAMP organoids when compared to luminal cell-derived organoids. Furthermore, we found MALAT1 gene fusions to be drivers of antiandrogen resistance in TRAMP mice through regulation of AR. Summarizing, TRAMP tumor cells exhibited primary resistance towards androgen inhibition enhanced through basal cell function and MALAT1 gene fusions. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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11 pages, 2114 KiB  
Article
Protection and Alleviated Inflammation Induced by Virus-like Particle Vaccines Containing Plasmodium berghei MSP-8, MSP-9 and RAP1
by Su-Hwa Lee, Ki-Back Chu, Hae-Ji Kang and Fu-Shi Quan
Vaccines 2022, 10(2), 203; https://doi.org/10.3390/vaccines10020203 - 27 Jan 2022
Cited by 2 | Viewed by 2169
Abstract
Virus-like particles (VLP) are a highly efficient vaccine platform used to present multiple antigenic proteins. Merozoite surface protein 8 (MSP-8), 9 (MSP-9) and rhoptry-associated protein 1 (RAP1) of Plasmodium berghei are the important proteins in erythrocyte invasion and the replication of parasites. In [...] Read more.
Virus-like particles (VLP) are a highly efficient vaccine platform used to present multiple antigenic proteins. Merozoite surface protein 8 (MSP-8), 9 (MSP-9) and rhoptry-associated protein 1 (RAP1) of Plasmodium berghei are the important proteins in erythrocyte invasion and the replication of parasites. In this study, we generated three VLPs expressing MSP-8, MSP-9 or RAP1 together with influenza virus matrix protein M1 as a core protein, and the protection and alleviated inflammation induced by VLP immunization were investigated. Mice were immunized with a mixture of three VLPs, MSP-8, MSP-9 and RAP1, and challenge-infected with P. berghei. As a result, VLPs immunization elicited higher levels of P. berghei or VLPs-specific IgG antibody responses in the sera upon boost compared to that upon prime and naive. Upon challenge infection with P. berghei, higher levels of CD4+ T cell and memory B cell responses in the spleen were also found in VLPs-immunized mice compared to non-immunized control. Importantly, VLP immunization significantly alleviated inflammatory cytokine responses (TNF-α, IFN-γ) both in the sera and spleen. VLP vaccine immunization also assisted in diminishing the parasitic burden in the peripheral blood and prolonged the survival of immunized mice. These results indicated that a VLPs vaccine containing MSP-8, MSP-9 and RAP1 could be a vaccine candidate for P. berghei infection. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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14 pages, 4759 KiB  
Article
Enhancing the Bioavailability and Efficacy of Vismodegib for the Control of Skin Cancer: In Vitro and In Vivo Studies
by Heba F. Salem, Amr Gamal, Haitham Saeed, Marwa Kamal and Alaa S. Tulbah
Pharmaceuticals 2022, 15(2), 126; https://doi.org/10.3390/ph15020126 - 21 Jan 2022
Cited by 11 | Viewed by 2580
Abstract
Skin cancer is the most frequent cancer throughout the world. Vismodegib (VSD) is a hedgehog blocker approved for the prevention and treatment of skin cancer. VSD, however, is poorly bioavailable and has been linked to side effects. This work focused on designing a [...] Read more.
Skin cancer is the most frequent cancer throughout the world. Vismodegib (VSD) is a hedgehog blocker approved for the prevention and treatment of skin cancer. VSD, however, is poorly bioavailable and has been linked to side effects. This work focused on designing a nano-invasome gel as a vehicle for enhancing the permeation, bioavailability, and efficacy of VSD. Additionally, the combined effect of terpenes and ethanol was studied on the permeation of VSD compared with liposomes. The prepared VSD-loaded invasomes (VLI) formulation included cineole (1%v/v), cholesterol (0.15%w/w), phospholipid (2%w/w), and ethanol (3%v/v) and displayed an entrapment efficiency of 87.73 ± 3.82%, a vesicle size of 188.27 ± 3.25 nm, and a steady-state flux of 9.83 ± 0.11 µg/cm2/h. The VLI formulation was vigorously stirred into a carbopol base before being characterized in vivo to investigate the permeation, bioavailability, and efficacy of VSD. The VLI gel enhanced the dermal permeation of VSD and, as a result, had 3.59 times higher bioavailability with excellent antitumor action as compared to oral VSD. In summary, as an alternative to oral administration for skin cancer treatment, invasomes are efficient carriers for delivering VSD and enhancing its transdermal flux into deep skin layers. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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16 pages, 3892 KiB  
Article
Hypoxia Preconditioned Serum (HPS)-Hydrogel Can Accelerate Dermal Wound Healing in Mice—An In Vivo Pilot Study
by Jun Jiang, Ursula Kraneburg, Ulf Dornseifer, Arndt F. Schilling, Ektoras Hadjipanayi, Hans-Günther Machens and Philipp Moog
Biomedicines 2022, 10(1), 176; https://doi.org/10.3390/biomedicines10010176 - 14 Jan 2022
Cited by 5 | Viewed by 2304
Abstract
The ability to use the body’s resources to promote wound repair is increasingly becoming an interesting area of regenerative medicine research. Here, we tested the effect of topical application of blood-derived hypoxia preconditioned serum (HPS) on wound healing in a murine wound model. [...] Read more.
The ability to use the body’s resources to promote wound repair is increasingly becoming an interesting area of regenerative medicine research. Here, we tested the effect of topical application of blood-derived hypoxia preconditioned serum (HPS) on wound healing in a murine wound model. Alginate hydrogels loaded with two different HPS concentrations (10 and 40%) were applied topically on full-thickness wounds created on the back of immunocompromised mice. We achieved a significant dose-dependent wound area reduction after 5 days in HPS-treated groups compared with no treatment (NT). On average, both HPS-10% and HPS-40% -treated wounds healed 1.4 days faster than NT. Healed tissue samples were investigated on post-operative day 15 (POD 15) by immunohistology and showed an increase in lymphatic vessels (LYVE-1) up to 45% with HPS-40% application, while at this stage, vascularization (CD31) was comparable in the HPS-treated and NT groups. Furthermore, the expression of proliferation marker Ki67 was greater on POD 15 in the NT-group compared to HPS-treated groups, in accordance with the earlier completion of wound healing observed in the latter. Collagen deposition was similar in all groups, indicating lack of scar tissue hypertrophy as a result of HPS-hydrogel treatment. These findings show that topical HPS application is safe and can accelerate dermal wound healing in mice. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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9 pages, 1592 KiB  
Article
Metabolic Status of Lean and Obese Zucker Rats Based on Untargeted and Targeted Metabolomics Analysis of Serum
by Stepan Melnyk and Reza Hakkak
Biomedicines 2022, 10(1), 153; https://doi.org/10.3390/biomedicines10010153 - 12 Jan 2022
Cited by 5 | Viewed by 1658
Abstract
Obesity is growing worldwide epidemic. Animal models can provide some clues about the etiology, development, prevention, and treatment of obesity. We examined and compared serum metabolites between seven lean (L) and seven obese (O) female Zucker rats to investigate the individual serum metabolic [...] Read more.
Obesity is growing worldwide epidemic. Animal models can provide some clues about the etiology, development, prevention, and treatment of obesity. We examined and compared serum metabolites between seven lean (L) and seven obese (O) female Zucker rats to investigate the individual serum metabolic profile. A combination of HPLC-UV, HPLC-ECD, and LC-MS revealed more than 400 peaks. The 50 highest quality peaks were selected as the focus of our study. Untargeted metabolomics analysis showed significantly higher mean peak heights for 20 peaks in L rats, generally distributed randomly, except for a cluster (peaks 44–50) where L showed stable dominancy over O. Only eight peaks were significantly higher in O rats. Peak height ratios between pairs of L and O rats were significantly higher at 199 positions in L rats and at 123 positions in O rats. Targeted metabolomics analysis showed significantly higher levels of methionine, cysteine, tryptophan, kynurenic acid, and cysteine/cystine ratio in L rats and significantly higher levels of cystine and tyrosine in O rats. These results contribute to a better understanding of systemic metabolic perturbations in the obese Zucker rat model, emphasizing the value of both whole metabolome and individual metabolic profiles in the design and interpretation of studies using animal models. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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7 pages, 759 KiB  
Article
The Chimeric Binjari-Zika Vaccine Provides Long-Term Protection against ZIKA Virus Challenge
by Jessamine E. Hazlewood, Bing Tang, Kexin Yan, Daniel J. Rawle, Jessica J. Harrison, Roy A. Hall, Jody Hobson-Peters and Andreas Suhrbier
Vaccines 2022, 10(1), 85; https://doi.org/10.3390/vaccines10010085 - 06 Jan 2022
Cited by 8 | Viewed by 2253
Abstract
We recently developed a chimeric flavivirus vaccine technology based on the novel insect-specific Binjari virus (BinJV) and used this to generate a chimeric ZIKV vaccine (BinJ/ZIKA-prME) that protected IFNAR-/- dams and fetuses from infection. Herein, we show that a single vaccination of [...] Read more.
We recently developed a chimeric flavivirus vaccine technology based on the novel insect-specific Binjari virus (BinJV) and used this to generate a chimeric ZIKV vaccine (BinJ/ZIKA-prME) that protected IFNAR-/- dams and fetuses from infection. Herein, we show that a single vaccination of IFNAR-/- mice with unadjuvanted BinJ/ZIKA-prME generated neutralizing antibody responses that were retained for 14 months. At 15 months post vaccination, mice were also completely protected against detectable viremia and substantial body weight loss after challenge with ZIKVPRVABC59. BinJ/ZIKA-prME vaccination thus provided long-term protective immunity without the need for adjuvant or replication of the vaccine in the vaccine recipient, both attractive features for a ZIKV vaccine. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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14 pages, 3016 KiB  
Article
GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats
by Ángel Zúñiga-Romero, Quetzali Rivera-Plata, Jesús Arrieta, Francisco Javier Flores-Murrieta, Juan Rodríguez-Silverio, Juan Gerardo Reyes-García, Juan Carlos Huerta-Cruz, Gustavo Ramírez-Martínez and Héctor Isaac Rocha-González
Pharmaceuticals 2022, 15(1), 67; https://doi.org/10.3390/ph15010067 - 05 Jan 2022
Cited by 3 | Viewed by 2098
Abstract
Orphan G-protein-coupled receptors (GPCR) comprise a large number of receptors which are widely distributed in the nervous system and represent an opportunity to identify new molecular targets in pain medicine. GPR55 and GPR119 are two orphan GPCR receptors whose physiological function is unclear. [...] Read more.
Orphan G-protein-coupled receptors (GPCR) comprise a large number of receptors which are widely distributed in the nervous system and represent an opportunity to identify new molecular targets in pain medicine. GPR55 and GPR119 are two orphan GPCR receptors whose physiological function is unclear. The aim was to explore the participation of spinal GPR55 and GPR119 in the processing of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Protein localization and modulation were measured by immunohistochemistry and western blotting, respectively. Intrathecal administration of CID16020046 (selective GPR55 antagonist) or AS1269574 (selective GPR119 agonist) produced a dose-dependent antiallodynic effect, whereas O1062 (GPR55 agonist) and G-protein antagonist peptide dose-dependently prevented the antiallodynic effect of CID16020046 and AS1269574, respectively. Both GPR55 and GPR119 receptors were expressed in spinal cord, dorsal root ganglia and sciatic nerve, but only GPR119 was downregulated after 14 days of spinal nerve ligation. Data suggest that GPR55 and GPR119 participate in the processing of neuropathic pain and could be useful targets to manage neuropathic pain disorders. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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18 pages, 4312 KiB  
Article
Vaccine Based on Dendritic Cells Electroporated with an Exogenous Ovalbumin Protein and Pulsed with Invariant Natural Killer T Cell Ligands Effectively Induces Antigen-Specific Antitumor Immunity
by Akihiro Watanabe, Kimihiro Yamashita, Mitsugu Fujita, Akira Arimoto, Masayasu Nishi, Shiki Takamura, Masafumi Saito, Kota Yamada, Kyosuke Agawa, Tomosuke Mukoyama, Masayuki Ando, Shingo Kanaji, Takeru Matsuda, Taro Oshikiri and Yoshihiro Kakeji
Cancers 2022, 14(1), 171; https://doi.org/10.3390/cancers14010171 - 30 Dec 2021
Cited by 2 | Viewed by 2477
Abstract
(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in [...] Read more.
(1) Background: Cancer vaccines are administered to induce cytotoxic CD8+ T cells (CTLs) specific for tumor antigens. Invariant natural killer T (iNKT) cells, the specific T cells activated by α-galactosylceramide (α-GalCer), play important roles in this process as they are involved in both innate and adaptive immunity. We developed a new cancer vaccine strategy in which dendritic cells (DCs) were loaded with an exogenous ovalbumin (OVA) protein by electroporation (EP) and pulsed with α-GalCer. (2) Methods: We generated bone marrow-derived DCs from C57BL/6 mice, loaded full-length ovalbumin proteins to the DCs by EP, and pulsed them with α-GalCer (OVA-EP-galDCs). The OVA-EP-galDCs were intravenously administered to C57BL/6 mice as a vaccine. We then investigated subsequent immune responses, such as the induction of iNKT cells, NK cells, intrinsic DCs, and OVA-specific CD8+ T cells, including tissue-resident memory T (TRM) cells. (3) Results: The OVA-EP-galDC vaccine efficiently rejected subcutaneous tumors in a manner primarily dependent on CD8+ T cells. In addition to the OVA-specific CD8+ T cells both in early and late phases, we observed the induction of antigen-specific TRM cells in the skin. (4) Conclusions: The OVA-EP-galDC vaccine efficiently induced antigen-specific antitumor immunity, which was sustained over time, as shown by the TRM cells. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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23 pages, 3253 KiB  
Article
Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin
by Aejin Lee, McKensie L. Mason, Tao Lin, Shashi Bhushan Kumar, Devan Kowdley, Jacob H. Leung, Danah Muhanna, Yuan Sun, Joana Ortega-Anaya, Lianbo Yu, Julie Fitzgerald, A. Courtney DeVries, Randy J. Nelson, Zachary M. Weil, Rafael Jiménez-Flores, Jon R. Parquette and Ouliana Ziouzenkova
Pharmaceutics 2022, 14(1), 81; https://doi.org/10.3390/pharmaceutics14010081 - 29 Dec 2021
Viewed by 3165
Abstract
Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to [...] Read more.
Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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16 pages, 4285 KiB  
Article
Overexpression of Interleukin-33 in Recombinant Rabies Virus Enhances Innate and Humoral Immune Responses through Activation of Dendritic Cell-Germinal Center Reactions
by Zhizhong Mi, Ling Zhao, Ming Sun, Ting Gao, Yong Wang, Baokun Sui and Yingying Li
Vaccines 2022, 10(1), 34; https://doi.org/10.3390/vaccines10010034 - 28 Dec 2021
Cited by 2 | Viewed by 1966
Abstract
Rabies is a zoonotic infectious disease caused by rabies virus (RABV), and its mortality rate is as high as 100%. Globally, an average of 60,000 people die from rabies each year. The most effective method to prevent and limit rabies is vaccination, but [...] Read more.
Rabies is a zoonotic infectious disease caused by rabies virus (RABV), and its mortality rate is as high as 100%. Globally, an average of 60,000 people die from rabies each year. The most effective method to prevent and limit rabies is vaccination, but it is currently expensive and inefficient, consisting of a 3-dose series of injections and requiring to be immunized annually. Therefore, it is urgent to develop a single dose of long-acting rabies vaccine. In this study, recombinant rabies virus (rRABV) overexpressing interleukin-33 (IL-33) was constructed and designated as rLBNSE-IL33, and its effect was evaluated in a mouse model. The results showed that rLBNSE-IL33 could enhance the quick production of RABV-induced immune antibodies as early as three days post immunization (dpi) through the activation of dendritic cells (DCs), a component of the innate immune system. Furthermore, rLBNSE-IL33 induced high-level virus-neutralizing antibodies (VNA) production that persisted for 8 weeks by regulating the T cell-dependent germinal center (GC) reaction, thus resulting in better protection against rabies. Our data suggest the IL-33 is a novel adjuvant that could be used to enhance innate and humoral immune responses by activating the DC-GC reaction, and thus, rLBNSE-IL33 could be developed as a safe and effective vaccine for animals. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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12 pages, 4292 KiB  
Article
Potential Protective Effect of Vitamin C on Qunalphos-Induced Cardiac Toxicity: Histological and Tissue Biomarker Assay
by Ayed A. Shati, Mohamed Samir A. Zaki, Youssef A. Alqahtani, Mohamed A. Haidara, Mubarak Al-Shraim, Amal F. Dawood and Refaat A. Eid
Biomedicines 2022, 10(1), 39; https://doi.org/10.3390/biomedicines10010039 - 24 Dec 2021
Cited by 4 | Viewed by 2770
Abstract
Insecticides and toxicants abound in nature, posing a health risk to humans. Concurrent exposure to many environmental contaminants has been demonstrated to harm myocardial performance and reduce cardiac oxidative stress. The purpose of this research was to study the protective effect of vitamin [...] Read more.
Insecticides and toxicants abound in nature, posing a health risk to humans. Concurrent exposure to many environmental contaminants has been demonstrated to harm myocardial performance and reduce cardiac oxidative stress. The purpose of this research was to study the protective effect of vitamin C (Vit C) on quinalphos (QP)-induced cardiac tissue damage in rats. Eighteen albino male rats were randomly categorised into three groups (n = 6). Control, QP group: rats received distilled water. QP insecticide treatment: an oral administration of QP incorporated in drinking water. QP + Vit C group: rats received QP and Vit C. All the experiments were conducted for ten days. Decline of cardiac antioxidant biomarkers catalase (CAT) and reduced glutathione (GPx) along with increased proinflammatory markers tumour necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) indicated oxidative and inflammatory damage to the heart following administration of QP when compared to control rats. The light microscopic and ultrastructure appearance of QP-treated cardiomyocytes exhibited cardiac damage. Administration of Vit C showed decreased oxidative and inflammatory biomarkers, confirmed with histological and electron microscopic examination. In conclusion, Vit C protected the heart from QP-induced cardiac damage due to decreased inflammation and oxidative stress. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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15 pages, 3347 KiB  
Article
In Vitro and In Vivo Bioequivalence Study of 3D-Printed Instant-Dissolving Levetiracetam Tablets and Subsequent Personalized Dosing for Chinese Children Based on Physiological Pharmacokinetic Modeling
by Xianfu Li, En Liang, Xiaoxuan Hong, Xiaolu Han, Conghui Li, Yuxi Wang, Zengming Wang and Aiping Zheng
Pharmaceutics 2022, 14(1), 20; https://doi.org/10.3390/pharmaceutics14010020 - 22 Dec 2021
Cited by 7 | Viewed by 2917
Abstract
Recently, the development of Binder Jet 3D printing technology has promoted the research and application of personalized formulations, which are especially useful for children’s medications. Additionally, physiological pharmacokinetic (PBPK) modeling can be used to guide drug development and drug dose selection. Multiple technologies [...] Read more.
Recently, the development of Binder Jet 3D printing technology has promoted the research and application of personalized formulations, which are especially useful for children’s medications. Additionally, physiological pharmacokinetic (PBPK) modeling can be used to guide drug development and drug dose selection. Multiple technologies can be used in combination to increase the safety and effectiveness of drug administration. In this study, we performed in vivo pharmacokinetic experiments in dogs with preprepared 3D-printed levetiracetam instant-dissolving tablets (LEV-IDTs). Bioequivalence analysis showed that the tablets were bioequivalent to commercially available preparations (Spritam®) for dogs. Additionally, we evaluated the bioequivalence of 3D-printed LEV-IDTs with Spritam® by a population-based simulation based on the established PBPK model of levetiracetam for Chinese adults. Finally, we established a PBPK model of oral levetiracetam in Chinese children by combining the physiological parameters of children, and we simulated the PK (pharmacokinetics) curves of Chinese children aged 4 and 6 years that were administered the drug to provide precise guidance on adjusting the dose according to the effective dose range of the drug. Briefly, utilizing both Binder jet 3D printing technology and PBPK models is a promising route for personalized drug delivery with various age groups. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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12 pages, 1941 KiB  
Article
mRNA Vaccine Protects against Zika Virus
by Lex G. Medina-Magües, Janina Gergen, Edith Jasny, Benjamin Petsch, Jaime Lopera-Madrid, Emily S. Medina-Magües, Cristhian Salas-Quinchucua and Jorge E. Osorio
Vaccines 2021, 9(12), 1464; https://doi.org/10.3390/vaccines9121464 - 10 Dec 2021
Cited by 21 | Viewed by 4307
Abstract
Zika virus (ZIKV), a mosquito-borne flavivirus, has recently triggered global concern due to severe health complications. In 2015, a large ZIKV outbreak occurred in the Americas and established a link between ZIKV and microcephaly in newborn babies, spontaneous abortion, persistent viremia, and Guillain–Barré [...] Read more.
Zika virus (ZIKV), a mosquito-borne flavivirus, has recently triggered global concern due to severe health complications. In 2015, a large ZIKV outbreak occurred in the Americas and established a link between ZIKV and microcephaly in newborn babies, spontaneous abortion, persistent viremia, and Guillain–Barré syndrome. While antivirals are being developed and prevention strategies focus on vector control, a safe and effective Zika vaccine remains unavailable. Messenger RNA (mRNA) vaccine technology has arisen as a flexible, simplified, and fast vaccine production platform. Here, we report on an mRNA vaccine candidate that encodes the pre-membrane and envelope (prM–E) glycoproteins of ZIKV strain Brazil SPH2015 and is encapsulated in lipid nanoparticles (LNPs). Our ZIKV prM–E mRNA-LNP vaccine candidate induced antibody responses that protected in AG129 mice deficient in interferon (IFN) alpha/beta/gamma (IFN-α/β/γ) receptors. Notably, a single administration of ZIKV prM–E mRNA-LNP protected against a lethal dose of ZIKV, while a two-dose strategy induced strong protective immunity. E-specific double-positive IFN-γ and TNF-α T-cells were induced in BALB/c mice after immunizations with a two-dose strategy. With the success of mRNA vaccine technology in facing the coronavirus (COVID-19) pandemic, our data support the development of prM–E RNActive® as a promising mRNA vaccine against Zika to counter future epidemics. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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17 pages, 4038 KiB  
Article
IL-20 Cytokines Are Involved in Epithelial Lesions Associated with Virus-Induced COPD Exacerbation in Mice
by Mélina Le Roux, Anaïs Ollivier, Gwenola Kervoaze, Timothé Beke, Laurent Gillet, Muriel Pichavant and Philippe Gosset
Biomedicines 2021, 9(12), 1838; https://doi.org/10.3390/biomedicines9121838 - 05 Dec 2021
Cited by 4 | Viewed by 2640
Abstract
(1) Background: viral infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are responsible for disease progression and mortality. Previous reports showed that IL-20 cytokines facilitate bacterial lung infection, but their production and their role in COPD and viral [...] Read more.
(1) Background: viral infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are responsible for disease progression and mortality. Previous reports showed that IL-20 cytokines facilitate bacterial lung infection, but their production and their role in COPD and viral infection has not yet been investigated. (2) Methods: C57BL/6 WT and IL-20 Rb KO mice were chronically exposed to air or cigarette smoke (CS) to mimic COPD. Cytokine production, antiviral response, inflammation and tissue damages were analyzed after PVM infection. (3) Results: CS exposure was associated with an increase in viral burden and antiviral response. PVM infection in CS mice enhanced IFN-γ, inflammation and tissue damage compared to Air mice. PVM infection and CS exposure induced, in an additive manner, IL-20 cytokines expression and the deletion of IL-20 Rb subunit decreased the expression of interferon-stimulated genes and the production of IFN-λ2/3, without an impact on PVM replication. Epithelial cell damages and inflammation were also reduced in IL-20 Rb-/- mice, and this was associated with reduced lung permeability and the maintenance of intercellular junctions. (4) Conclusions: PVM infection and CS exposure additively upregulates the IL-20 pathway, leading to the promotion of epithelial damages. Our data in our model of viral exacerbation of COPD identify IL-20 cytokine as a potential therapeutic target. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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25 pages, 1952 KiB  
Systematic Review
Preclinical Imaging Evaluation of miRNAs’ Delivery and Effects in Breast Cancer Mouse Models: A Systematic Review
by Francesca Maria Orlandella, Luigi Auletta, Adelaide Greco, Antonella Zannetti and Giuliana Salvatore
Cancers 2021, 13(23), 6020; https://doi.org/10.3390/cancers13236020 - 30 Nov 2021
Cited by 4 | Viewed by 1971
Abstract
Background: We have conducted a systematic review focusing on the advancements in preclinical molecular imaging to study the delivery and therapeutic efficacy of miRNAs in mouse models of breast cancer. Methods: A systematic review of English articles published in peer-reviewed journals using PubMed, [...] Read more.
Background: We have conducted a systematic review focusing on the advancements in preclinical molecular imaging to study the delivery and therapeutic efficacy of miRNAs in mouse models of breast cancer. Methods: A systematic review of English articles published in peer-reviewed journals using PubMed, EMBASE, BIOSIS™ and Scopus was performed. Search terms included breast cancer, mouse, mice, microRNA(s) and miRNA(s). Results: From a total of 2073 records, our final data extraction was from 114 manuscripts. The most frequently used murine genetic background was Balb/C (46.7%). The most frequently used model was the IV metastatic model (46.8%), which was obtained via intravenous injection (68.9%) in the tail vein. Bioluminescence was the most used frequently used tool (64%), and was used as a surrogate for tumor growth for efficacy treatment or for the evaluation of tumorigenicity in miRNA-transfected cells (29.9%); for tracking, evaluation of engraftment and for response to therapy in metastatic models (50.6%). Conclusions: This review provides a systematic and focused analysis of all the information available and related to the imaging protocols with which to test miRNA therapy in an in vivo mice model of breast cancer, and has the purpose of providing an important tool to suggest the best preclinical imaging protocol based on available evidence. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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14 pages, 2944 KiB  
Article
Ultrasound and Microbubbles Enhance Uptake of Doxorubicin in Murine Kidneys
by Oystein Eikrem, Spiros Kotopoulis, Mihaela Popa, Mireia Mayoral Safont, Kjell Ove Fossan, Sabine Leh, Lea Landolt, Janka Babickova, Oddrun Anita Gudbrandsen, Odd Helge Gilja, Bettina Riedel, Jan Schjøtt, Emmet McCormack and Hans-Peter Marti
Pharmaceutics 2021, 13(12), 2038; https://doi.org/10.3390/pharmaceutics13122038 - 29 Nov 2021
Cited by 2 | Viewed by 2017
Abstract
The use of ultrasound and microbubble-enhanced drug delivery, commonly referred to as sonoporation, has reached numerous clinical trials and has shown favourable results. Nevertheless, the microbubbles and acoustic path also pass through healthy tissues. To date, the majority of studies have focused on [...] Read more.
The use of ultrasound and microbubble-enhanced drug delivery, commonly referred to as sonoporation, has reached numerous clinical trials and has shown favourable results. Nevertheless, the microbubbles and acoustic path also pass through healthy tissues. To date, the majority of studies have focused on the impact to diseased tissues and rarely evaluated the impact on healthy and collateral tissue. The aim of this study was to test the effect and feasibility of low-intensity sonoporation on healthy kidneys in a mouse model. In our work here, we used a clinical diagnostic ultrasound system (GE Vivid E9) with a C1-5 ultrasound transducer combined with a software modification for 20-µs-long pulses to induce the ultrasound-guided drug delivery of doxorubicin (DOX) in mice kidneys in combination with SonoVue® and Sonazoid™ microbubbles. The acoustic output settings were within the commonly used diagnostic ranges. Sonoporation with SonoVue® resulted in a significant decrease in weight vs. DOX alone (p = 0.0004) in the first nine days, whilst all other comparisons were not significant. Ultrasound alone resulted in a 381% increase in DOX uptake vs. DOX alone (p = 0.0004), whilst SonoVue® (p = 0.0001) and Sonazoid™ (p < 0.0001) further increased the uptake nine days after treatment (419% and 493%, respectively). No long-standing damage was observed in the kidneys via histology. In future sonoporation and drug uptake studies, we therefore suggest including an “ultrasound alone” group to verify the actual contribution of the individual components of the procedure on the drug uptake and to perform collateral damage studies to ensure there is no negative impact of low-intensity sonoporation on healthy tissues. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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17 pages, 2876 KiB  
Article
A Patient-Derived Xenograft Model of Dedifferentiated Endometrial Carcinoma: A Proof-of-Concept Study for the Identification of New Molecularly Informed Treatment Approaches
by Chiao-Yun Lin, Ren-Chin Wu, Chen-Yang Huang, Chyong-Huey Lai, An-Shine Chao, Hsin-Pai Li, Chia-Lung Tsai, Elizabeth Joo-Wen Kuek, Cheng-Lung Hsu and Angel Chao
Cancers 2021, 13(23), 5962; https://doi.org/10.3390/cancers13235962 - 26 Nov 2021
Cited by 4 | Viewed by 2150
Abstract
Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow [...] Read more.
Conventional treatment of dedifferentiated endometrial carcinoma (DEC)–an uncommon and highly aggressive uterine malignancy–is beset by high failure rates. A line of research that holds promise to overcome these limitations is tailored treatments targeted on specific molecular alterations. However, suitable preclinical platforms to allow a reliable implementation of this approach are still lacking. Here, we developed a patient-derived xenograft (PDX) model for preclinical testing of investigational drugs informed by molecular data. The model–termed PDX-mLung was established in mice implanted with lung metastatic lesions obtained from a patient with DEC. Histologic and whole-exome genetic analyses revealed a high degree of identity between PDX-mLung and the patient’s parental lesions (both primary DEC and lung metastases). Interestingly, molecular analyses revealed that PDX-mLung harbored druggable alterations including a FGFR2 mutation and CCNE2 amplification. Targeted combined treatment with the FGFR inhibitor lenvatinib and the cell cycle inhibitor palbociclib was found to exert synergistic therapeutic effects against in vivo tumor growth. Based on the results of RNA sequencing, lenvatinib and palbociclib were found to exert anti-tumor effects by interfering interferon signaling and activating hormonal pathways, respectively. Collectively, these data provide proof-of-concept evidence on the value of PDX models for preclinical testing of molecularly informed drug therapy in difficult-to-treat human malignancies. Further clinical research is needed to examine more rigorously the potential usefulness of the lenvatinib and palbociclib combination in patients with DEC. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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19 pages, 5094 KiB  
Article
Anti-Tumor Activity of Expanded PBMC-Derived NK Cells by Feeder-Free Protocol in Ovarian Cancer
by Minhua Chen, Yutong Li, Yu Wu, Siqi Xie, Jie Ma, Jingjing Yue, Rong Lv, Zhigang Tian, Fang Fang and Weihua Xiao
Cancers 2021, 13(22), 5866; https://doi.org/10.3390/cancers13225866 - 22 Nov 2021
Cited by 7 | Viewed by 2991
Abstract
Natural killer (NK) cells have shown great therapeutic potential against a wide range of cancers due to their pan-specific target recognition. Numerous reports indicate that NK cell immunotherapy is an effective therapeutic approach for treating hematological malignancies, but shows limited effects against solid [...] Read more.
Natural killer (NK) cells have shown great therapeutic potential against a wide range of cancers due to their pan-specific target recognition. Numerous reports indicate that NK cell immunotherapy is an effective therapeutic approach for treating hematological malignancies, but shows limited effects against solid tumors. In this study, several models of ovarian cancer (OC) were used to test the anti-cancer effects of NK cells derived from human peripheral blood mononuclear cells and expanded using a feeder cell-free expansion system (eNKs). The results show that eNKs exhibit potent inhibitory activity on tumor growth in different ovarian cancer xenograft mice (i.e., solid tumors, abdominal metastatic tumors, and ascites), importantly, in a dose-dependent manner. Moreover, adoptive transfer of eNKs resulted in significant reduction in ascites formation in OC peritoneal tumor models, and especially in reducing intraperitoneal ascites. We found that eNKs could migrate to the tumor site, retain their activity, and proliferate to maintain high cell counts in cutaneous xenograft mice. In addition, when increased the infusion with a high dose of 12 × 107 cells/mouse, Graft-versus-host disease could be induced by eNK. These data show that eNK cell immunotherapy could be a promising treatment strategy for ovarian cancers, including solid tumors and ascites. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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15 pages, 2442 KiB  
Article
Gas6 Ameliorates Inflammatory Response and Apoptosis in Bleomycin-Induced Acute Lung Injury
by Bo-Min Kim, Ye-Ji Lee, Youn-Hee Choi, Eun-Mi Park and Jihee Lee Kang
Biomedicines 2021, 9(11), 1674; https://doi.org/10.3390/biomedicines9111674 - 12 Nov 2021
Cited by 6 | Viewed by 2340
Abstract
Acute lung injury (ALI) is characterized by alveolar damage, lung edema, and exacerbated inflammatory response. Growth arrest-specific protein 6 (Gas6) mediates many different functions, including cell survival, proliferation, inflammatory signaling, and apoptotic cell clearance (efferocytosis). The role of Gas6 in bleomycin (BLM)-induced ALI [...] Read more.
Acute lung injury (ALI) is characterized by alveolar damage, lung edema, and exacerbated inflammatory response. Growth arrest-specific protein 6 (Gas6) mediates many different functions, including cell survival, proliferation, inflammatory signaling, and apoptotic cell clearance (efferocytosis). The role of Gas6 in bleomycin (BLM)-induced ALI is unknown. We investigated whether exogenous administration of mouse recombinant Gas6 (rGas6) has anti-inflammatory and anti-apoptotic effects on BLM-induced ALI. Compared to mice treated with only BLM, the administration of rGas6 reduced the secretion of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2, and increased the secretion of hepatocyte growth factor in bronchoalveolar lavage (BAL) fluid. rGas6 administration also reduced BLM-induced inflammation and apoptosis as evidenced by reduced neutrophil recruitment into the lungs, total protein levels in BAL fluid, caspase-3 activity, and TUNEL-positive lung cells in lung tissue. Apoptotic cell clearance by alveolar macrophages was also enhanced in mice treated with both BLM and rGas6 compared with mice treated with only BLM. rGas6 also had pro-resolving and anti-apoptotic effects in mouse bone marrow-derived macrophages and alveolar epithelial cell lines stimulated with BLM in vitro. These findings indicate that rGas6 may play a protective role in BLM-induced ALI. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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21 pages, 5475 KiB  
Article
Anti-Staphylococcus aureus Single-Chain Fragment Variables Play a Protective Anti-Inflammatory Role In Vitro and In Vivo
by Lei Zhang, Xin Ye, Yan Zhang, Fengqing Wang, Fanqing Zhang, Yan Jia, Dangjin Wu, Kalbinur Tohti, Manling Cheng and Jianguo Zhu
Vaccines 2021, 9(11), 1300; https://doi.org/10.3390/vaccines9111300 - 09 Nov 2021
Cited by 2 | Viewed by 1993 | Correction
Abstract
Staphylococcus aureus is a causative agent of bovine mastitis, capable of causing significant economic losses to the dairy industry worldwide. This study focuses on obtaining single-chain fragment variables (scFvs) against the virulence factors of S. aureus and evaluates the protective effect of scFvs [...] Read more.
Staphylococcus aureus is a causative agent of bovine mastitis, capable of causing significant economic losses to the dairy industry worldwide. This study focuses on obtaining single-chain fragment variables (scFvs) against the virulence factors of S. aureus and evaluates the protective effect of scFvs on bovine mammary epithelial (MAC-T) cells and mice mammary gland tissues infected by S. aureus. After five rounds of bio-panning, four scFvs targeting four virulence factors of S. aureus were obtained. The complementarity-determining regions (CDRs) of these scFvs exhibited significant diversities, especially CDR3 of the VH domain. In vitro, each of scFvs was capable of inhibiting S. aureus growth and reducing the damage of MAC-T cells infected by S. aureus. Preincubation of MAC-T cells with scFvs could significantly attenuate the effect of apoptosis and necrosis compared with the negative control group. In vivo, the qPCR and ELISA results demonstrated that scFvs reduced the transcription and expression of Tumor Necrosis Factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8, and IL-18. Histopathology and myeloperoxidase (MPO) results showed that scFvs ameliorated the histopathological damages and reduced the inflammatory cells infiltration. The overall results demonstrated the positive anti-inflammatory effect of scFvs, revealing the potential role of scFvs in the prevention and treatment of S. aureus infections. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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14 pages, 2731 KiB  
Article
Lung Deposition of Surfactant Delivered via a Dedicated Laryngeal Mask Airway in Piglets
by Anders Nord, Doris Cunha-Goncalves, Rikard Linnér, Federico Bianco, Fabrizio Salomone, Francesca Ricci, Marta Lombardini, Massimo Micaglio, Daniele Trevisanuto and Valeria Perez-de-Sa
Pharmaceutics 2021, 13(11), 1858; https://doi.org/10.3390/pharmaceutics13111858 - 04 Nov 2021
Cited by 3 | Viewed by 1731
Abstract
It is unknown if the lung deposition of surfactant administered via a catheter placed through a laryngeal mask airway (LMA) is equivalent to that obtained by bolus instillation through an endotracheal tube. We compare the lung deposition of surfactant delivered via two types [...] Read more.
It is unknown if the lung deposition of surfactant administered via a catheter placed through a laryngeal mask airway (LMA) is equivalent to that obtained by bolus instillation through an endotracheal tube. We compare the lung deposition of surfactant delivered via two types of LMA with the standard technique of endotracheal instillation. 25 newborn piglets on continuous positive airway pressure support (CPAP) were randomized into three groups: 1—LMA-camera (integrated camera and catheter channel; catheter tip below vocal cords), 2—LMA-standard (no camera, no channel; catheter tip above the glottis), 3—InSurE (Intubation, Surfactant administration, Extubation; catheter tip below end of endotracheal tube). All animals received 100 mg·kg−1 of poractant alfa mixed with 99mTechnetium-nanocolloid. Surfactant deposition was measured by gamma scintigraphy as a percentage of the administered dose. The median (range) total lung surfactant deposition was 68% (10–85), 41% (5–88), and 88% (67–92) in LMA-camera, LMA-standard, and InSurE, respectively, which was higher (p < 0.05) in the latter. The deposition in the stomach and nasopharynx was higher with the LMA-standard. The surfactant deposition via an LMA was lower than that obtained with InSurE. Although not statistically significant, introducing the catheter below the vocal cords under visual control with an integrated camera improved surfactant LMA delivery by 65%. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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1 pages, 691 KiB  
Correction
Correction: Sioud et al. Evaluation of In Vitro Phototoxicity of a Minibody-IR700 Conjugate Using Monolayer and Multicellular Tumor Spheroid Models. Cancers 2021, 13, 3356
by Mouldy Sioud, Petras Juzenas, Qindong Zhang, Andrius Kleinauskas and Qian Peng
Cancers 2021, 13(21), 5513; https://doi.org/10.3390/cancers13215513 - 03 Nov 2021
Cited by 1 | Viewed by 1128
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
13 pages, 9416 KiB  
Article
High Expression of PPM1D Induces Tumors Phenotypically Similar to TP53 Loss-of-Function Mutations in Mice
by Jelena Milosevic, Susanne Fransson, Miklos Gulyas, Thale K. Olsen, Gabriel Gallo-Oller, Diana Treis, Lotta H. M. Elfman, Margareta Wilhelm, Tommy Martinsson, Ninib Baryawno, Per Kogner and John Inge Johnsen
Cancers 2021, 13(21), 5493; https://doi.org/10.3390/cancers13215493 - 31 Oct 2021
Cited by 5 | Viewed by 2342
Abstract
PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice [...] Read more.
PPM1D is a negative regulator of p53 and genomic aberrations resulting in increased activity of PPM1D have been observed in cancers of different origins, indicating that PPM1D has oncogenic properties. We established a transgenic mouse model overexpressing PPM1D and showed that these mice developed a wide variety of cancers. PPM1D-expressing mice developed tumors phenotypically and genetically similar to tumors in mice with dysfunctional p53. T-cell lymphoblastic lymphoma was the most frequent cancer observed in these mice (55%) followed by adenocarcinomas (24%), leukemia (12%) and other solid tumors including neuroblastoma. Characterization of T-cell lymphomas in mice overexpressing PPM1D demonstrates Pten-deletion and p53-accumulation similar to mice with p53 loss-of-function. Also, Notch1 mutations which are recurrently observed in T-cell acute lymphoblastic lymphoma (T-ALL) were frequently detected in PPM1D-transgenic mice. Hence, PPM1D acts as an oncogenic driver in connection with cellular stress, suggesting that the PPM1D gene status and expression levels should be investigated in TP53 wild-type tumors. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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20 pages, 43915 KiB  
Article
Ethoxyquin Inhibits the Progression of Murine Ehrlich Ascites Carcinoma through the Inhibition of Autophagy and LDH
by Fekria Tayel, Magdy E. Mahfouz, Afrah F. Salama and Mohammed A. Mansour
Biomedicines 2021, 9(11), 1526; https://doi.org/10.3390/biomedicines9111526 - 23 Oct 2021
Cited by 4 | Viewed by 2172
Abstract
Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use [...] Read more.
Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene Bcl-2 and by a significant increase in the expression of apoptotic genes (BAX and caspase-3). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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14 pages, 3397 KiB  
Review
Intraductal Papillary Mucinous Neoplasms of the Pancreas: A Review of Their Genetic Characteristics and Mouse Models
by Jin Li, Tao Wei, Jian Zhang and Tingbo Liang
Cancers 2021, 13(21), 5296; https://doi.org/10.3390/cancers13215296 - 22 Oct 2021
Cited by 5 | Viewed by 5727
Abstract
The intraductal papillary mucinous neoplasm (IPMN) is attracting research attention because of its increasing incidence and proven potential to progress into invasive pancreatic ductal adenocarcinoma (PDAC). In this review, we summarized the key signaling pathways or protein complexes (GPCR, TGF, SWI/SNF, WNT, and [...] Read more.
The intraductal papillary mucinous neoplasm (IPMN) is attracting research attention because of its increasing incidence and proven potential to progress into invasive pancreatic ductal adenocarcinoma (PDAC). In this review, we summarized the key signaling pathways or protein complexes (GPCR, TGF, SWI/SNF, WNT, and PI3K) that appear to be involved in IPMN pathogenesis. In addition, we collected information regarding all the genetic mouse models that mimic the human IPMN phenotype with specific immunohistochemistry techniques. The mouse models enable us to gain insight into the complex mechanism of the origin of IPMN, revealing that it can be developed from both acinar cells and duct cells according to different models. Furthermore, recent genomic studies describe the potential mechanism by which heterogeneous IPMN gives rise to malignant carcinoma through sequential, branch-off, or de novo approaches. The most intractable problem is that the risk of malignancy persists to some extent even if the primary IPMN is excised with a perfect margin, calling for the re-evaluation and improvement of diagnostic, pre-emptive, and therapeutic measures. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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17 pages, 14501 KiB  
Article
Dissecting Abdominal Aortic Aneurysm Is Aggravated by Genetic Inactivation of LIGHT (TNFSF14)
by Andrea Herrero-Cervera, Carla Espinós-Estévez, Susana Martín-Vañó, Alida Taberner-Cortés, María Aguilar-Ballester, Ángela Vinué, Laura Piqueras, Sergio Martínez-Hervás and Herminia González-Navarro
Biomedicines 2021, 9(11), 1518; https://doi.org/10.3390/biomedicines9111518 - 22 Oct 2021
Cited by 4 | Viewed by 2260
Abstract
Abdominal aortic aneurysm (AAA), is a complex disorder characterized by vascular vessel wall remodeling. LIGHT (TNFSF14) is a proinflammatory cytokine associated with vascular disease. In the present study, the impact of genetic inactivation of Light was investigated in dissecting AAA induced by angiotensin [...] Read more.
Abdominal aortic aneurysm (AAA), is a complex disorder characterized by vascular vessel wall remodeling. LIGHT (TNFSF14) is a proinflammatory cytokine associated with vascular disease. In the present study, the impact of genetic inactivation of Light was investigated in dissecting AAA induced by angiotensin II (AngII) in the Apolipoprotein E-deficient (Apoe−/−) mice. Studies in aortic human (ah) vascular smooth muscle cells (VSMC) to study potential translation to human pathology were also performed. AngII-treated Apoe−/−Light−/− mice displayed increased abdominal aorta maximum diameter and AAA severity compared with Apoe−/− mice. Notably, reduced smooth muscle α-actin+ area and Acta2 and Col1a1 gene expression were observed in AAA from Apoe−/−Light−/− mice, suggesting a loss of VSMC contractile phenotype compared with controls. Decreased Opn and augmented Sox9 expression, which are associated with detrimental and non-contractile osteochondrogenic VSMC phenotypes, were also seen in AngII-treated Apoe−/−Light−/− mouse AAA. Consistent with a role of LIGHT preserving VSMC contractile characteristics, LIGHT-treatment of ahVSMCs diminished the expression of SOX9 and of the pluripotency marker CKIT. These effects were partly mediated through lymphotoxin β receptor (LTβR) as the silencing of its gene ablated LIGHT effects on ahVSMCs. These studies suggest a protective role of LIGHT through mechanisms that prevent VSMC trans-differentiation in an LTβR-dependent manner. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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12 pages, 2393 KiB  
Article
Protective Potential of an Autogenous Vaccine in an Aerogenous Model of Escherichia coli Infection in Broiler Breeders
by Sofie Kromann, Rikke Heidemann Olsen, Anders Miki Bojesen, Henrik Elvang Jensen and Ida Thøfner
Vaccines 2021, 9(11), 1233; https://doi.org/10.3390/vaccines9111233 - 22 Oct 2021
Cited by 7 | Viewed by 2100
Abstract
In poultry, Escherichia coli is a common cause of high-cost infections. Consequently, autogenous vaccines are often used despite limited and conflicting evidence on their effectiveness have been presented. The present study aimed to investigate the efficacy of a commonly used autogenous vaccine, previously [...] Read more.
In poultry, Escherichia coli is a common cause of high-cost infections. Consequently, autogenous vaccines are often used despite limited and conflicting evidence on their effectiveness have been presented. The present study aimed to investigate the efficacy of a commonly used autogenous vaccine, previously deemed ineffective, in an aerosol model of colibacillosis. Methods: Broiler breeders (n = 47) were randomly allocated to one of four groups (vaccinated and unvaccinated birds receiving an autogenous vaccine or sterile saline intramuscularly) and challenged with either aerosolised E. coli or vehicle at 29 weeks of age. Two days following inoculation, the birds were euthanised, thoroughly necropsied, and samples for bacteriology and histopathology were collected. Results: Vaccinated birds had a significantly lower bacteriology score compared to the unvaccinated group challenged with E. coli (p < 0.01) and a lower overall air sac lesion score (p < 0.05). Overall lung and spleen lesion scores only differed significantly between the unvaccinated E. coli challenged group compared to the vehicle inoculated groups. The overall gross pathology score was 2.8 and 1.95 in the unvaccinated and vaccinated E. coli challenge groups, respectively, whereas the vaccinated vehicle group had a score of 0.9 and the unvaccinated vehicle group a score of 1. Conclusions: A protective effect of an autogenous vaccine was found utilising an aerogenous model of colibacillosis through multiple methods of evaluation. The findings encourage the continued use of autogenous vaccines and underlines the necessity of discriminative experimental models with high predictive validity when evaluating vaccine interventions. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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10 pages, 1100 KiB  
Article
A Live Probiotic Vaccine Prototype Based on Conserved Influenza a Virus Antigens Protect Mice against Lethal Influenza Virus Infection
by Daria Mezhenskaya, Irina Isakova-Sivak, Tatiana Gupalova, Elena Bormotova, Eugenia Kuleshevich, Tatiana Kramskaya, Galina Leontieva, Larisa Rudenko and Alexander Suvorov
Biomedicines 2021, 9(11), 1515; https://doi.org/10.3390/biomedicines9111515 - 21 Oct 2021
Cited by 8 | Viewed by 1885
Abstract
Background: Due to the highly variable nature of the antigenic properties of the influenza virus, many efforts have been made to develop broadly reactive influenza vaccines. Various vaccine platforms have been explored to deliver conserved viral antigens to the target cells to induce [...] Read more.
Background: Due to the highly variable nature of the antigenic properties of the influenza virus, many efforts have been made to develop broadly reactive influenza vaccines. Various vaccine platforms have been explored to deliver conserved viral antigens to the target cells to induce cross-reactive immune responses. Here, we assessed the feasibility of using Enterococcus faecium L3 as a bacterial vector for oral immunization against influenza virus. Methods: we generated two vaccine prototypes by inserting full-length HA2 (L3-HA2) protein or its long alpha helix (LAH) domain in combination with four M2e tandem repeats (L3-LAH+M2e) into genome of E.faecium L3 probiotic strain. The immunogenicity and protective potential of these oral vaccines were assessed in a lethal challenge model in BALB/c mice. Results: as expected, both vaccine prototypes induced HA stem-targeting antibodies, whereas only L3-LAH+4M2e vaccine induced M2e-specific antibody. The L3-HA2 vaccine partially protected mice against lethal challenge with two H1N1 heterologous viruses, while 100% of animals in the L3-LAH+4M2e vaccine group survived in both challenge experiments, and there was significant protection against weight loss in this group, compared to the L3 vector-immunized control mice. Conclusions: the recombinant enterococcal strain L3-LAH+4M2e can be considered as a promising live probiotic vaccine candidate for influenza prevention and warrants further evaluation in relevant pre-clinical models. Full article
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16 pages, 7280 KiB  
Article
Zoledronate Bound to Ceramics Increases Ectopic Bone Volume Induced by rhBMP6 Delivered in Autologous Blood Coagulum in Rats
by Nikola Stokovic, Natalia Ivanjko, Igor Erjavec, Anita Breski, Mihaela Peric and Slobodan Vukicevic
Biomedicines 2021, 9(10), 1487; https://doi.org/10.3390/biomedicines9101487 - 16 Oct 2021
Cited by 4 | Viewed by 1985
Abstract
Autologous bone graft substitute (ABGS) containing rhBMP6 in autologous blood coagulum (ABC) with synthetic ceramics is a novel therapeutic solution for bone repair. The aim of this study was to investigate whether the application of Zoledronate (ZOL) with ABGS might enhance the properties [...] Read more.
Autologous bone graft substitute (ABGS) containing rhBMP6 in autologous blood coagulum (ABC) with synthetic ceramics is a novel therapeutic solution for bone repair. The aim of this study was to investigate whether the application of Zoledronate (ZOL) with ABGS might enhance the properties of newly formed bone. The effect of ZOL on bone induction was tested in a rat subcutaneous implant model. ZOL bound to synthetic ceramics was added into ABGS implants, and the quantity, quality, and longevity of the induced bone were assessed by micro-CT, histomorphometry, and histology over a period of 365 days. Local use of ZOL in the ABGS implants with ceramics had no influence on the bone volume (BV) on day 14 but subsequently significantly increased BV on days 35, 50, 105, 140, and 365 compared to the control implants. Locally applied ZOL had a similar effect in all of the applied doses (2–20 µg), while its systemic use on stimulating the BV of newly induced bone by ABGS depended on the time of application. BV was increased when ZOL was applied systemically on day 14 but had no effect when applied on day 35. The administration of ZOL bound to ceramics in ABGS increased and maintained the BV over a period of one year, offering a novel bone tissue engineering strategy for treating bone defects and spinal fusions. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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21 pages, 2714 KiB  
Article
Magnetically Assisted Drug Delivery of Topical Eye Drops Maintains Retinal Function In Vivo in Mice
by Marco Bassetto, Daniel Ajoy, Florent Poulhes, Cathy Obringer, Aurelie Walter, Nadia Messadeq, Amir Sadeghi, Jooseppi Puranen, Marika Ruponen, Mikko Kettunen, Elisa Toropainen, Arto Urtti, Hélène Dollfus, Olivier Zelphati and Vincent Marion
Pharmaceutics 2021, 13(10), 1650; https://doi.org/10.3390/pharmaceutics13101650 - 09 Oct 2021
Cited by 5 | Viewed by 2432
Abstract
Barded-Biedl syndrome (BBS) is a rare genetic disorder with an unmet medical need for retinal degeneration. Small-molecule drugs were previously identified to slow down the apoptosis of photoreceptors in BBS mouse models. Clinical translation was not practical due to the necessity of repetitive [...] Read more.
Barded-Biedl syndrome (BBS) is a rare genetic disorder with an unmet medical need for retinal degeneration. Small-molecule drugs were previously identified to slow down the apoptosis of photoreceptors in BBS mouse models. Clinical translation was not practical due to the necessity of repetitive invasive intravitreal injections for pediatric populations. Non-invasive methods of retinal drug targeting are a prerequisite for acceptable adaptation to the targeted pediatric patient population. Here, we present the development and functional testing of a non-invasive, topical, magnetically assisted delivery system, harnessing the ability of magnetic nanoparticles (MNPs) to cargo two drugs (guanabenz and valproic acid) with anti-unfolded protein response (UPR) properties towards the retina. Using magnetic resonance imaging (MRI), we showed the MNPs’ presence in the retina of Bbs wild-type mice, and their photoreceptor localization was validated using transmission electron microscopy (TEM). Subsequent electroretinogram recordings (ERGs) demonstrated that we achieved beneficial biological effects with the magnetically assisted treatment translating the maintained light detection in Bbs−/− mice (KO). To our knowledge, this is the first demonstration of efficient magnetic drug targeting in the photoreceptors in vivo after topical administration. This non-invasive, needle-free technology expands the application of SMDs for the treatment of a vast spectrum of retinal degenerations and other ocular diseases. Full article
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17 pages, 4497 KiB  
Article
Reviewing the Effects of Skin Manipulations on Adult Newt Limb Regeneration: Implications for the Subcutaneous Origin of Axial Pattern Formation
by Martin Miguel Casco-Robles, Kayo Yasuda, Kensuke Yahata, Fumiaki Maruo and Chikafumi Chiba
Biomedicines 2021, 9(10), 1426; https://doi.org/10.3390/biomedicines9101426 - 09 Oct 2021
Cited by 3 | Viewed by 2618
Abstract
Newts are unique salamanders that can regenerate their limbs as postmetamorphic adults. In order to regenerate human limbs as newts do, it is necessary to determine whether the cells homologous to those contributing to the limb regeneration of adult newts also exist in [...] Read more.
Newts are unique salamanders that can regenerate their limbs as postmetamorphic adults. In order to regenerate human limbs as newts do, it is necessary to determine whether the cells homologous to those contributing to the limb regeneration of adult newts also exist in humans. Previous skin manipulation studies in larval amphibians have suggested that stump skin plays a pivotal role in the axial patterning of regenerating limbs. However, in adult newts such studies are limited, though they are informative. Therefore, in this article we have conducted skin manipulation experiments such as rotating the skin 180° around the proximodistal axis of the limb and replacing half of the skin with that of another location on the limb or body. We found that, contrary to our expectations, adult newts robustly regenerated limbs with a normal axial pattern regardless of skin manipulation, and that the appearance of abnormalities was stochastic. Our results suggest that the tissue under the skin, rather than the skin itself, in the intact limb is of primary importance in ensuring the normal axial pattern formation in adult newt limb regeneration. We propose that the important tissues are located in small areas underlying the ventral anterior and ventral posterior skin. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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16 pages, 4347 KiB  
Article
The Impact of Improving Dermal Permeation on the Efficacy and Targeting of Liposome Nanoparticles as a Potential Treatment for Breast Cancer
by Heba F. Salem, Amr Gamal, Haitham Saeed and Alaa S. Tulbah
Pharmaceutics 2021, 13(10), 1633; https://doi.org/10.3390/pharmaceutics13101633 - 06 Oct 2021
Cited by 9 | Viewed by 2128
Abstract
Breast cancer is the most frequent malignancy in women. This work focuses on developing deformable liposomes as a potential carrier for breast cancer treatment and studying the impact of improving dermal permeation on the efficacy and targeting of liposomes. Raloxifene (RXF), an oestrogen [...] Read more.
Breast cancer is the most frequent malignancy in women. This work focuses on developing deformable liposomes as a potential carrier for breast cancer treatment and studying the impact of improving dermal permeation on the efficacy and targeting of liposomes. Raloxifene (RXF), an oestrogen antagonist, was used as a model drug. Using Box–Behnken design, different formulations of RXF-loaded deformable liposome (RLDL) were prepared using different propylene glycol, phospholipid and cholesterol concentrations. The percentage of entrapment efficiency (Y1), particle size (Y2), zeta potential (Y3) and steady-state flux (Y4) of the prepared formulations were all evaluated. Y1 and Y4 were significantly increased and Y2 and Y3 were significantly decreased when the propylene glycol concentration was increased. The optimization was obtained and the optimum formulation was that including phospholipid (1.40% w/w), cholesterol (0.15% w/w) and propylene glycol (10% v/v). The selected optimum formulation displayed a % EE of 78.34 ± 1.04% with a steady-state flux of 4.21 ± 0.02 µg/cm2/h. In order to investigate bioavailability, antitumor effectiveness and permeation, the optimum formulation was selected and included in a carbopol gel. The optimum gel formulation had 2.77 times higher bioavailability and, as a result, considerable antitumor action as compared to oral RXF. In conclusion, optimum RLDL gel may be an effective breast cancer treatment. Full article
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18 pages, 6351 KiB  
Article
SDCBP Modulates Stemness and Chemoresistance in Head and Neck Squamous Cell Carcinoma through Src Activation
by Cristina Mir, Yoelsis Garcia-Mayea, Laia Garcia, Pol Herrero, Nuria Canela, Rocío Tabernero, Juan Lorente, Josep Castellvi, Eva Allonca, Juana García-Pedrero, Juan Pablo Rodrigo, Ángel Carracedo and Matilde Esther LLeonart
Cancers 2021, 13(19), 4952; https://doi.org/10.3390/cancers13194952 - 01 Oct 2021
Cited by 9 | Viewed by 2568
Abstract
To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. [...] Read more.
To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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21 pages, 2441 KiB  
Article
Maraviroc Prevents HCC Development by Suppressing Macrophages and the Liver Progenitor Cell Response in a Murine Chronic Liver Disease Model
by Adam M. Passman, Robyn P. Strauss, Sarah B. McSpadden, Megan Finch-Edmondson, Neil Andrewartha, Ken H. Woo, Luke A. Diepeveen, Weihao Zhao, Joaquín Fernández-Irigoyen, Enrique Santamaría, Laura Medina-Ruiz, Martyna Szpakowska, Andy Chevigné, Hyerin Park, Rodrigo Carlessi, Janina E. E. Tirnitz-Parker, José R. Blanco, Roslyn London, Bernard A. Callus, Caryn L. Elsegood, Murray V. Baker, Alfredo Martínez, George C. T. Yeoh and Laura Ochoa-Callejeroadd Show full author list remove Hide full author list
Cancers 2021, 13(19), 4935; https://doi.org/10.3390/cancers13194935 - 30 Sep 2021
Cited by 8 | Viewed by 3335
Abstract
Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a [...] Read more.
Maraviroc (MVC), a CCR5 antagonist, reduces liver fibrosis, injury and tumour burden in mice fed a hepatocarcinogenic diet, suggesting it has potential as a cancer therapeutic. We investigated the effect of MVC on liver progenitor cells (LPCs) and macrophages as both have a role in hepatocarcinogenesis. Mice were fed the hepatocarcinogenic choline-deficient, ethionine-supplemented diet (CDE) ± MVC, and immunohistochemistry, RNA and protein expression were used to determine LPC and macrophage abundance, migration and related molecular mechanisms. MVC reduced LPC numbers in CDE mice by 54%, with a smaller reduction seen in macrophages. Transcript and protein abundance of LPC-associated markers correlated with this reduction. The CDE diet activated phosphorylation of AKT and STAT3 and was inhibited by MVC. LPCs did not express Ccr5 in our model; in contrast, macrophages expressed high levels of this receptor, suggesting the effect of MVC is mediated by targeting macrophages. MVC reduced CD45+ cells and macrophage migration in liver and blocked the CDE-induced transition of liver macrophages from an M1- to M2-tumour-associated macrophage (TAM) phenotype. These findings suggest MVC has potential as a re-purposed therapeutic agent for treating chronic liver diseases where M2-TAM and LPC numbers are increased, and the incidence of HCC is enhanced. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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11 pages, 640 KiB  
Article
Artificial Light at Night Reduces Anxiety-like Behavior in Female Mice with Exacerbated Mammary Tumor Growth
by William H. Walker II, Raegan M. Kvadas, Laura E. May, Jennifer A. Liu, Jacob R. Bumgarner, James C. Walton, A. Courtney DeVries, Robert T. Dauchy, David E. Blask and Randy J. Nelson
Cancers 2021, 13(19), 4860; https://doi.org/10.3390/cancers13194860 - 28 Sep 2021
Cited by 6 | Viewed by 2332
Abstract
Artificial light at night (ALAN) is a pervasive phenomenon. Although initially assumed to be innocuous, recent research has demonstrated its deleterious effects on physiology and behavior. Exposure to ALAN is associated with disruptions to sleep/wake cycles, development of mood disorders, metabolic disorders, and [...] Read more.
Artificial light at night (ALAN) is a pervasive phenomenon. Although initially assumed to be innocuous, recent research has demonstrated its deleterious effects on physiology and behavior. Exposure to ALAN is associated with disruptions to sleep/wake cycles, development of mood disorders, metabolic disorders, and cancer. However, the influence of ALAN on affective behavior in tumor-bearing mice has not been investigated. We hypothesize that exposure to ALAN accelerates mammary tumor growth and predict that ALAN exacerbates negative affective behaviors in tumor-bearing mice. Adult (>8 weeks) female C3H mice received a unilateral orthotropic injection of FM3A mouse mammary carcinoma cells (1.0 × 105 in 100 μL) into the fourth inguinal mammary gland. Nineteen days after tumor inoculation, mice were tested for sucrose preference (anhedonia-like behavior). The following day, mice were subjected to an open field test (anxiety-like behavior), followed by forced swim testing (depressive-like behavior). Regardless of tumor status, mice housed in ALAN increased body mass through the first ten days. Tumor-bearing ALAN-housed mice demonstrated reduced latency to tumor onset (day 5) and increased terminal tumor volume (day 21). Exposure to ALAN reduced sucrose preference independent of tumor status. Additionally, tumor-bearing mice housed in dark nights demonstrated significantly increased anxiety-like behavior that was normalized via housing in ALAN. Together, these data reaffirm the negative effects of ALAN on tumorigenesis and demonstrate the potential anxiolytic effect of ALAN in the presence of mammary tumors. Full article
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15 pages, 4182 KiB  
Article
Chronic Restraint Stress-Induced Muscle Atrophy Leads to Fatigue in Mice by Inhibiting the AMPK Signaling Pathway
by Zhi Wang, Tianji Xia, Suwei Jin, Xinmin Liu, Ruile Pan, Mingzhu Yan and Qi Chang
Biomedicines 2021, 9(10), 1321; https://doi.org/10.3390/biomedicines9101321 - 26 Sep 2021
Cited by 6 | Viewed by 2286
Abstract
Currently, an increasing number of people are suffering from fatigue due to the state of their lifestyles, such as sedentary work in a relatively small space, irregular sleep patterns, or the lack of movement and exercise. The present study was designed to simulate [...] Read more.
Currently, an increasing number of people are suffering from fatigue due to the state of their lifestyles, such as sedentary work in a relatively small space, irregular sleep patterns, or the lack of movement and exercise. The present study was designed to simulate the occurrence of fatigue in the above populations through a chronic restraint stress (CRS) model, and to reveal its dynamic processes and potential underlying molecular mechanisms. ICR mice were subjected to 8 h of restraint stress each day for 5, 10, or 15 days. It was found that the weight-loaded swimming performance, grip strength, and locomotor activity of the mice all decreased under CRS treatment, and that up to 15 days of CRS induced notable fatigue. Gastrocnemius muscle atrophy and some abnormal biochemical parameters related to fatigue under CRS were observed. Furthermore, transcriptome data showed that the changes in muscle cell metabolism and mitochondrial dysfunction were associated with the AMPK signaling pathway in CRS-treated mice. Western blotting analysis of the AMPK/PGC-1α signaling pathway revealed that CRS could decrease mitochondrial biogenesis and reduce the numbers of type I skeletal muscle fibers in the gastrocnemius of mice. CRS could also block the protective mitophagic flux to inhibit the abnormal clearance of damaged mitochondria. Our study suggests a critical link between muscle atrophy and CRS-induced fatigue in mice, suggesting that the pharmacological promotion of muscle and mitochondrial function can be used as a treatment for stress-induced fatigue. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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21 pages, 6991 KiB  
Article
An Insulin-like Growth Factor-1 Conjugated Bombyx mori Silk Fibroin Film for Diabetic Wound Healing: Fabrication, Physicochemical Property Characterization, and Dosage Optimization In Vitro and In Vivo
by Meng-Jin Lin, Mei-Chun Lu, Yun-Chen Chan, Yu-Fen Huang and Hwan-You Chang
Pharmaceutics 2021, 13(9), 1459; https://doi.org/10.3390/pharmaceutics13091459 - 13 Sep 2021
Cited by 8 | Viewed by 2540
Abstract
This study aimed to develop a silk fibroin (SF)-film for the treatment of chronic diabetic wounds. Silk fibroin was purified through a newly developed heating degumming (HD) process and casted on a hydrophobic surface to form SF-films. The process allowed the fabricated film [...] Read more.
This study aimed to develop a silk fibroin (SF)-film for the treatment of chronic diabetic wounds. Silk fibroin was purified through a newly developed heating degumming (HD) process and casted on a hydrophobic surface to form SF-films. The process allowed the fabricated film to achieve a 42% increase in transparency and a 32% higher proliferation rate for BALB/3T3 fibroblasts compared to that obtained by conventional alkaline degumming treatment. Fourier transform infrared analysis demonstrated that secondary structure was retained in both HD- and alkaline degumming-derived SF preparations, although the crystallinity of beta-sheet in SF-film after the HD processing was slightly increased. This study also investigated whether conjugating insulin-like growth factor-1 (IGF-1) would promote diabetic wound healing and what the optimal dosage is. Using BALB/3T3 cells grown in hyperglycemic medium as a model, it was demonstrated that the optimal IGF-1 dosage to promote the cell growth was approximately 0.65 pmol. Further analysis of wound healing in a diabetic mouse model indicated that SF-film loaded with 3.25 pmol of IGF-1 showed significantly superior wound closure, a 13% increase at the 13th day after treatment relative to treatment with 65 pmol of free IGF-1. Improvement in diabetic wound healing was exerted synergistically by SF-film and IGF-1, as reflected by parameters including levels of re-epithelialization, epithelial tissue area, and angiogenesis. Finally, IGF-1 increased the epithelial tissue area and micro-vessel formation in a dose-dependent manner in a low dosage range (3.25 pmol) when loaded to SF-films. Together, these results strongly suggest that SF-film produced using HD and loaded with a low dosage of IGF-1 is a promising dressing for diabetic wound therapy. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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16 pages, 2470 KiB  
Article
Decreased MicroRNA-150 Exacerbates Neuronal Apoptosis in the Diabetic Retina
by Fei Yu, Michael L. Ko and Gladys Y.-P. Ko
Biomedicines 2021, 9(9), 1135; https://doi.org/10.3390/biomedicines9091135 - 01 Sep 2021
Cited by 6 | Viewed by 1911
Abstract
Diabetic retinopathy (DR) is a chronic complication associated with diabetes and the number one cause of blindness in working adults in the US. More than 90% of diabetic patients have obesity-associated type 2 diabetes (T2D), and 60% of T2D patients will develop DR. [...] Read more.
Diabetic retinopathy (DR) is a chronic complication associated with diabetes and the number one cause of blindness in working adults in the US. More than 90% of diabetic patients have obesity-associated type 2 diabetes (T2D), and 60% of T2D patients will develop DR. Photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. However, how diabetic insults cause photoreceptor apoptosis remains unclear. In this study, obesity-associated T2D mice and cultured photoreceptors were used to investigate how decreased microRNA-150 (miR-150) and its downstream target were involved in photoreceptor apoptosis. In the T2D retina, miR-150 was decreased with its target ETS-domain transcription factor (ELK1) and phosphorylated ELK1 at threonine 417 (pELK1T417) upregulated. In cultured photoreceptors, treatments with palmitic acid (PA), to mimic a high-fat environment, decreased miR-150 but upregulated ELK1, pELK1T417, and the translocation of pELK1T417 from the cytoplasm to the cell nucleus. Deletion of miR-150 (miR-150−/−) exacerbates T2D- or PA-induced photoreceptor apoptosis. Blocking the expression of ELK1 with small interfering RNA (siRNA) for Elk1 did not rescue PA-induced photoreceptor apoptosis. Translocation of pELK1T417 from cytoplasm-to-nucleus appears to be the key step of diabetic insult-elicited photoreceptor apoptosis. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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10 pages, 2354 KiB  
Article
Acetylated Diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol in Autoimmune Arthritis and Interstitial Lung Disease in SKG Mice
by Doo-Ho Lim, Eun-Ju Lee, Hee-Seop Lee, Do Hoon Kim, Jae-Hyun Lee, Mi Ryeong Jeong, Seokchan Hong, Chang-Keun Lee, Bin Yoo, Jeehee Youn and Yong-Gil Kim
Biomedicines 2021, 9(9), 1095; https://doi.org/10.3390/biomedicines9091095 - 27 Aug 2021
Cited by 2 | Viewed by 1945
Abstract
Acetylated diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is a lipid molecule from the antlers of sika deer that might reduce inflammation by effectively controlling neutrophil infiltration, endothelial permeability and inflammatory chemokine production. Therefore, we evaluated the modulatory effect of PLAG on arthritis and interstitial lung disease [...] Read more.
Acetylated diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is a lipid molecule from the antlers of sika deer that might reduce inflammation by effectively controlling neutrophil infiltration, endothelial permeability and inflammatory chemokine production. Therefore, we evaluated the modulatory effect of PLAG on arthritis and interstitial lung disease (ILD) in an autoimmune arthritis model. We injected curdlan into SKG mice and PLAG was orally administered every day from 3 weeks to 20 weeks after the curdlan injection. The arthritis score was measured every week after the curdlan injection. At 20 weeks post-injection, the lung specimens were evaluated with H&E, Masson’s trichrome and multiplexed immunofluorescent staining. Serum cytokines were also analyzed using a Luminex multiple cytokine assay. PLAG administration decreased the arthritis score until 8 weeks after the curdlan injection. However, the effect was not sustained thereafter. A lung histology revealed severe inflammation and fibrosis in the curdlan-induced SKG mice, which was attenuated in the PLAG-treated mice. Furthermore, immunofluorescent staining of the lung tissue showed a GM-CSF+ neutrophil accumulation and a decreased citrullinated histone 3 expression after PLAG treatment. PLAG also downregulated the levels of IL-6 and TNF-α and upregulated the level of sIL-7Rα, an anti-fibrotic molecule. Our results indicate that PLAG might have a preventative effect on ILD development through the resolution of NETosis in the lung. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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16 pages, 4276 KiB  
Article
Albumin Fusion at the N-Terminus or C-Terminus of HM-3 Leads to Improved Pharmacokinetics and Bioactivities
by Ting Li, Han-Zi Zhang, Guang-Fei Ge, Zhao-Rong Yue, Ru-Yue Wang, Qian Zhang, Yan Gu, Mei-Juan Song, Wen-Bo Li, Min-Zhi Ma, Mei-Zhu Wang, Hui Yang, Yang Li and Hong-Yu Li
Biomedicines 2021, 9(9), 1084; https://doi.org/10.3390/biomedicines9091084 - 25 Aug 2021
Cited by 1 | Viewed by 2527
Abstract
HM-3, an integrin antagonist, exhibits anti-tumor biological responses and therefore has potential as a therapeutic polypeptide. However, the clinical applications of HM-3 are limited by its short half-life. In this study, we genetically fused human serum albumin (HSA) to the N or C-terminus [...] Read more.
HM-3, an integrin antagonist, exhibits anti-tumor biological responses and therefore has potential as a therapeutic polypeptide. However, the clinical applications of HM-3 are limited by its short half-life. In this study, we genetically fused human serum albumin (HSA) to the N or C-terminus of HM-3 to improve HM-3 pharmacokinetics. HM-3/HSA proteins were successfully expressed in Pichia pastoris and displayed improved pharmacokinetic properties and stability. Among them, the half-life of HM-3-HSA was longer than HSA-HM-3. In vitro, the IC50 values of HSA-HM-3 and HM-3-HSA were 0.38 ± 0.14 μM and 0.25 ± 0.08 μM in B16F10 cells, respectively. In vivo, the inhibition rates of B16F10 tumor growth were 36% (HSA-HM-3) and 56% (HM-3-HSA), respectively, indicating antitumor activity of HM-3-HSA was higher than HSA-HM-3. In conclusion, these results suggested that the HM-3/HSA fusion protein might be potential candidate HM-3 agent for treatment of melanoma and when HSA was fused at the C-terminus of HM-3, the fusion protein had a higher stability and activity. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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18 pages, 1800 KiB  
Review
Gait Analysis Using Animal Models of Peripheral Nerve and Spinal Cord Injuries
by Gheorghita Isvoranu, Emilia Manole and Monica Neagu
Biomedicines 2021, 9(8), 1050; https://doi.org/10.3390/biomedicines9081050 - 19 Aug 2021
Cited by 11 | Viewed by 3037
Abstract
The present review discusses recent data regarding rodent models of spinal cord and peripheral nerve injuries in terms of gait analysis using the CatWalk system (CW), an automated and exceptionally reliable system for assessing gait abnormalities and motor coordination. CW is a good [...] Read more.
The present review discusses recent data regarding rodent models of spinal cord and peripheral nerve injuries in terms of gait analysis using the CatWalk system (CW), an automated and exceptionally reliable system for assessing gait abnormalities and motor coordination. CW is a good tool for both studying improvements in the walking of animals after suffering a peripheral nerve and spinal cord lesion and to select the best therapies and procedures after tissue destruction, given that it provides objective and quantifiable data. Most studies using CW for gait analysis that were published in recent years focus on injuries inflicted in the peripheral nerve, spinal cord, and brain. CW has been used in the assessment of rodent motor function through high-resolution videos, whereby specialized software was used to measure several aspects of the animal’s gait, and the main characteristics of the automated system are presented here. CW was developed to assess footfall and gait changes, and it can calculate many parameters based on footprints and time. However, given the multitude of parameters, it is necessary to evaluate which are the most important under the employed experimental circumstances. By selecting appropriate animal models and evaluating peripheral nerve and spinal cord lesion regeneration using standardized methods, suggestions for new therapies can be provided, which represents the translation of this methodology into clinical application. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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24 pages, 8022 KiB  
Article
Phytogalactolipid dLGG Inhibits Mouse Melanoma Brain Metastasis through Regulating Oxylipin Activity and Re-Programming Macrophage Polarity in the Tumor Microenvironment
by Chung-Chih Yang, Meng-Ting Chang, Cheng-Kuei Chang and Lie-Fen Shyur
Cancers 2021, 13(16), 4120; https://doi.org/10.3390/cancers13164120 - 16 Aug 2021
Cited by 4 | Viewed by 2786
Abstract
Current conventional cancer therapies for melanoma brain metastasis (MBM) remain ineffective. In this study, we demonstrated the bioefficacy of a phyto-glyceroglycolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) alone, or in combination with liposomal doxorubicin (Lip-DOX) or Avastin against MBM in a [...] Read more.
Current conventional cancer therapies for melanoma brain metastasis (MBM) remain ineffective. In this study, we demonstrated the bioefficacy of a phyto-glyceroglycolipid, 1,2-di-O-α-linolenoyl-3-O-β-galactopyranosyl-sn-glycerol (dLGG) alone, or in combination with liposomal doxorubicin (Lip-DOX) or Avastin against MBM in a syngeneic B16BM4COX−2/Luc brain-seeking melanoma mouse model. Treatment with dLGG–10, dLGG–25, dLGG–10 + Avastin–5, Lipo-DOX–2, dLGG–10 + Lipo-DOX–2 or Lipo-DOX–2 + Avastin–5 suppressed, respectively, 17.9%, 59.1%, 55.7%, 16.2%, 44.5% and 72.4% of MBM in mice relative to the untreated tumor control. Metastatic PD-L1+ melanoma cells, infiltration of M2-like macrophages and CD31+ endothelial cells, and high expression levels of 15-LOX/CYP450 4A enzymes in the brain tumor microenvironment of the tumor control mice were significantly attenuated in dLGG-treated mice; conversely, M1-like resident microglia and cytotoxic T cells were increased. A lipidomics study showed that dLGG promoted B16BM4 cells to secrete oxylipins 9,10-/12,13-EpOMEs into the culture medium. Furthermore, the conditioned medium of B16BM4 cells pretreated with dLGG or 9,10-EpOMEs + 12,13-EpOMEs drove M2-like macrophages to polarize into M1-like macrophages in vitro. An ex vivo 3D-culture assay further demonstrated that dLGG, 9,10-EpOME or 9,10-EpOME + 12,13-EpOME pretreatment attenuated B16BM4 cells invading brain tissue, and prevented microglia/macrophages infiltrating into the interface of melanoma plug and brain organ/tissue. In summary, this report provides a novel therapeutic strategy and mechanistic insights into phytogalactolipid dLGG for combating MBM. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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13 pages, 2940 KiB  
Article
Discrepancy in the Usage of GFAP as a Marker of Satellite Glial Cell Reactivity
by Kjeld Morten Mohr, Lone Tjener Pallesen, Mette Richner and Christian Bjerggaard Vaegter
Biomedicines 2021, 9(8), 1022; https://doi.org/10.3390/biomedicines9081022 - 16 Aug 2021
Cited by 17 | Viewed by 4009
Abstract
Satellite glial cells (SGCs) surrounding the neuronal somas in peripheral sensory ganglia are sensitive to neuronal stressors, which induce their reactive state. It is believed that such induced gliosis affects the signaling properties of the primary sensory neurons and is an important component [...] Read more.
Satellite glial cells (SGCs) surrounding the neuronal somas in peripheral sensory ganglia are sensitive to neuronal stressors, which induce their reactive state. It is believed that such induced gliosis affects the signaling properties of the primary sensory neurons and is an important component of the neuropathic phenotype leading to pain and other sensory disturbances. Efforts to understand and manipulate such gliosis relies on reliable markers to confirm induced SGC reactivity and ultimately the efficacy of targeted intervention. Glial fibrillary acidic protein (GFAP) is currently the only widely used marker for such analyses. However, we have previously described the lack of SGC upregulation of GFAP in a mouse model of sciatic nerve injury, suggesting that GFAP may not be a universally suitable marker of SGC gliosis across species and experimental models. To further explore this, we here investigate the regulation of GFAP in two different experimental models in both rats and mice. We found that whereas GFAP was upregulated in both rodent species in the applied inflammation model, only the rat demonstrated increased GFAP in SGCs following sciatic nerve injury; we did not observe any such GFAP upregulation in the mouse model at either protein or mRNA levels. Our results demonstrate an important discrepancy between species and experimental models that prevents the usage of GFAP as a universal marker for SGC reactivity. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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29 pages, 9510 KiB  
Article
Rifaximin Prevents T-Lymphocytes and Macrophages Infiltration in Cerebellum and Restores Motor Incoordination in Rats with Mild Liver Damage
by Tiziano Balzano, Paola Leone, Gergana Ivaylova, M. Carmen Castro, Lestteriel Reyes, Chusé Ramón, Michele Malaguarnera, Marta Llansola and Vicente Felipo
Biomedicines 2021, 9(8), 1002; https://doi.org/10.3390/biomedicines9081002 - 12 Aug 2021
Cited by 15 | Viewed by 2600
Abstract
In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is triggered by a shift in peripheral inflammation, promoting lymphocyte infiltration into the brain. Rifaximin improves neurological function in MHE by normalizing peripheral inflammation. Patients who died with steatohepatitis showed T-lymphocyte infiltration and neuroinflammation [...] Read more.
In patients with liver cirrhosis, minimal hepatic encephalopathy (MHE) is triggered by a shift in peripheral inflammation, promoting lymphocyte infiltration into the brain. Rifaximin improves neurological function in MHE by normalizing peripheral inflammation. Patients who died with steatohepatitis showed T-lymphocyte infiltration and neuroinflammation in the cerebellum, suggesting that MHE may already occur in these patients. The aims of this work were to assess, in a rat model of mild liver damage similar to steatohepatitis, whether: (1) the rats show impaired motor coordination in the early phases of liver damage; (2) this is associated with changes in the immune system and infiltration of immune cells into the brain; and (3) rifaximin improves motor incoordination, associated with improved peripheral inflammation, reduced infiltration of immune cells and neuroinflammation in the cerebellum, and restoration of the alterations in neurotransmission. Liver damage was induced by carbon tetrachloride (CCl4) injection over four weeks. Peripheral inflammation, immune cell infiltration, neuroinflammation, and neurotransmission in the cerebellum and motor coordination were assessed. Mild liver damage induces neuroinflammation and altered neurotransmission in the cerebellum and motor incoordination. These alterations are associated with increased TNFa, CCL20, and CX3CL1 in plasma and cerebellum, IL-17 and IL-15 in plasma, and CCL2 in cerebellum. This promotes T-lymphocyte and macrophage infiltration in the cerebellum. Early treatment with rifaximin prevents the shift in peripheral inflammation, immune cell infiltration, neuroinflammation, and motor incoordination. This report provides new clues regarding the mechanisms of the beneficial effects of rifaximin, suggesting that early rifaximin treatment could prevent neurological impairment in patients with steatohepatitis. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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19 pages, 3731 KiB  
Article
Protective and Therapeutic Effects of an IL-15:IL-15Rα-Secreting Cell-Based Cancer Vaccine Using a Baculovirus System
by Van Anh Do-Thi, Hayyoung Lee, Hye Jin Jeong, Jie-Oh Lee and Young Sang Kim
Cancers 2021, 13(16), 4039; https://doi.org/10.3390/cancers13164039 - 11 Aug 2021
Cited by 2 | Viewed by 2748
Abstract
This study reports the use of the BacMam system to deliver and express self-assembling IL-15 and IL-15Rα genes to murine B16F10 melanoma and CT26 colon cancer cells. BacMam-based IL-15 and IL-15Rα were well-expressed and assembled to form the biologically functional IL-15:IL-15Rα complex. Immunization [...] Read more.
This study reports the use of the BacMam system to deliver and express self-assembling IL-15 and IL-15Rα genes to murine B16F10 melanoma and CT26 colon cancer cells. BacMam-based IL-15 and IL-15Rα were well-expressed and assembled to form the biologically functional IL-15:IL-15Rα complex. Immunization with this IL-15:IL-15Rα cancer vaccine delayed tumor growth in mice by inducing effector memory CD4+ and CD8+ cells and effector NK cells which are tumor-infiltrating. It caused strong antitumor immune responses of CD8+ effector cells in a tumor-antigen specific manner both in vitro and in vivo and significantly attenuated Treg cells which a control virus-infected cancer vaccine could induce. Post-treatment with this cancer vaccine after a live cancer cell injection also prominently delayed the growth of the tumor. Collectively, we demonstrate a vaccine platform consisting of BacMam virus-infected B16F10 or CT26 cancer cells that secrete IL-15:IL-15Rα. This study is the first demonstration of a functionally competent soluble IL-15:IL-15Rα complex-related cancer vaccine using a baculovirus system and advocates that the BacMam system can be used as a secure and rapid method of producing a protective and therapeutic cancer vaccine. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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17 pages, 2493 KiB  
Article
Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy
by Amelia J. Hessheimer, Jordi Vengohechea, Lilia Martínez de la Maza, Javier Muñoz, Marina Vendrell, Josep Martí Sanahuja, Alba Torroella, Farah Adel Al Shwely, Francisco Riquelme, César Muñoz, Rocío García, Pilar Taurá and Constantino Fondevila
Cancers 2021, 13(16), 3989; https://doi.org/10.3390/cancers13163989 - 07 Aug 2021
Viewed by 2294
Abstract
Liver resection treats primary and secondary liver tumors, though clinical applicability is limited by the remnant liver mass and quality. Herein, major hepatic resections were performed in pigs to define changes associated with sufficient and insufficient remnants and improve liver-specific outcomes with somatostatin [...] Read more.
Liver resection treats primary and secondary liver tumors, though clinical applicability is limited by the remnant liver mass and quality. Herein, major hepatic resections were performed in pigs to define changes associated with sufficient and insufficient remnants and improve liver-specific outcomes with somatostatin therapy. Three experimental groups were performed: 75% hepatectomy (75H), 90% hepatectomy (90H), and 90% hepatectomy + somatostatin (90H + SST). Animals were followed for 24 h (N = 6) and 5 d (N = 6). After hepatectomy, portal pressure gradient was higher in 90H versus 75H and 90H + SST (8 (3–13) mmHg vs. 4 (2–6) mmHg and 4 (2–6) mmHg, respectively, p < 0.001). After 24 h, changes were observed in 90H associated with stellate cell activation and collapse of sinusoidal lumen. Collagen chain type 1 alpha 1 mRNA expression was higher, extracellular matrix width less, and percentage of collagen-staining areas greater at 24 h in 90H versus 75H and 90H + SST. After 5 d, remnant liver mass was higher in 75H and 90H + SST versus 90H, and Ki-67 immunostaining was higher in 90H + SST versus 75H and 90H. As well, more TUNEL-staining cells were observed in 90H versus 75H and 90H + SST at 5 d. Perioperative somatostatin modified portal pressure, injury, apoptosis, and stellate cell activation, stemming changes related to hepatic fibrogenesis seen in liver remnants not receiving treatment. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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18 pages, 2927 KiB  
Article
Hyperbaric Oxygen Therapy Alleviates the Autoimmune Encephalomyelitis via the Reduction of IL-17a and GM-Csf Production of Autoreactive T Cells as Well as Boosting the Immunosuppressive IL-10 in the Central Nervous System Tissue Lesions
by Hsin-Ying Clair Chiou, Shu-Hung Huang, Chih-Hsing Hung, Su-Min Tsai, Hui-Ru Kuo, Yu-Rui Huang, Jiunn-Wei Wang, Szu-Chia Chen, Chao-Hung Kuo, Deng-Chyang Wu, Shau-Ku Huang, Shih-Hsien Hsu and Ming-Hong Lin
Biomedicines 2021, 9(8), 943; https://doi.org/10.3390/biomedicines9080943 - 02 Aug 2021
Cited by 3 | Viewed by 2633
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease mainly caused by autoreactive T cells, followed by neuronal demyelination and disabling paralysis. Hyperbaric oxygen therapy (HBOT) is usually an adjunct to therapy for the treatment of neurological disorders. However, it remains still controversial whether [...] Read more.
Multiple sclerosis (MS) is a chronic autoimmune disease mainly caused by autoreactive T cells, followed by neuronal demyelination and disabling paralysis. Hyperbaric oxygen therapy (HBOT) is usually an adjunct to therapy for the treatment of neurological disorders. However, it remains still controversial whether HBOT is an effective option for the treatment of MS. Experimental autoimmune encephalomyelitis (EAE) is a well-studied mouse model investigated for the MS pathogenesis and the efficacy of the therapeutic intervention. Both encephalitogenic Th1 and Th17 are pivotal T cell subsets immunopathogenically producing several disease-initiating/modifying cytokines in the central nervous system (CNS) lesions to further exacerbate/ameliorate the progression of EAE or MS. However, it remains unclear whether HBOT modulates the context of T helper cell subsets in CNS lesions. We employed EAE in the presence of HBOT to assess whether disease amelioration is attributed to alterations of CNS-infiltrating T cell subsets. Our results demonstrated that semi-therapeutic HBOT significantly alleviated the progression of EAE, at least, via the suppression of Th17 response, the downregulation of CD4 T helper cells expressing GM-CSF or TNF-α, and the boosting of immunomodulatory IL-4 or IL-10-expressed CD4 T cells in the CNS lesions. Conclusively, HBOT attenuated EAE through the modulation of T cell responses in an earlier stage. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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14 pages, 5242 KiB  
Article
IGF1R as a Potential Pharmacological Target in Allergic Asthma
by Elvira Alfaro-Arnedo, Icíar P. López, Sergio Piñeiro-Hermida, Álvaro C. Ucero, Francisco J. González-Barcala, Francisco J. Salgado and José G. Pichel
Biomedicines 2021, 9(8), 912; https://doi.org/10.3390/biomedicines9080912 - 29 Jul 2021
Cited by 6 | Viewed by 2988 | Correction
Abstract
Background: Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Although Insulin-like growth factor 1 receptor (IGF1R) was found to be involved in asthma, its pharmacological inhibition has not previously been investigated in this [...] Read more.
Background: Asthma is a chronic lung disease characterized by reversible airflow obstruction, airway hyperresponsiveness (AHR), mucus overproduction and inflammation. Although Insulin-like growth factor 1 receptor (IGF1R) was found to be involved in asthma, its pharmacological inhibition has not previously been investigated in this pathology. We aimed to determine if therapeutic targeting of IGF1R ameliorates allergic airway inflammation in a murine model of asthma. Methods: C57BL/6J mice were challenged by house dust mite (HDM) extract or PBS for four weeks and therapeutically treated with the IGF1R tyrosine kinase inhibitor (TKI) NVP-ADW742 (NVP) once allergic phenotype was established. Results: Lungs of HDM-challenged mice exhibited a significant increase in phospho-IGF1R levels, incremented AHR, airway remodeling, eosinophilia and allergic inflammation, as well as altered pulmonary surfactant expression, all of being these parameters counteracted by NVP treatment. HDM-challenged lungs also displayed augmented expression of the IGF1R signaling mediator p-ERK1/2, which was greatly reduced upon treatment with NVP. Conclusions: Our results demonstrate that IGF1R could be considered a potential pharmacological target in murine HDM-induced asthma and a candidate biomarker in allergic asthma. Full article
(This article belongs to the Topic Animal Model in Biomedical Research)
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