Topic Editors

Pathobiology and Extracellular Vesicle Research Group, School of Life Sciences, University of Westminster, London W1W 6UW, UK
Prof. Dr. Jameel M. Inal
Biosciences Research Group, School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield AL10 9AB, UK

Animal Models of Human Disease 2.0

Abstract submission deadline
closed (30 June 2024)
Manuscript submission deadline
31 August 2024
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16021

Topic Information

Dear Colleagues, 

The use of animal models of human disease is critical for furthering our understanding of disease mechanisms, for the discovery of novel targets for treatment, and for translational research. This Topic aims to collect state-of-the-art primary research studies and review articles from international experts and leading groups using animal models to study human diseases. Submissions are welcome on a wide range of animal models and pathologies, including infectious disease, acute injury, regeneration, cancer, autoimmunity, and degenerative and chronic disease.

Prof. Dr. Sigrun Lange
Prof. Dr. Jameel M. Inal
Topic Editors

Keywords

  • animal models
  • human disease
  • pathology
  • pathobiology
  • chronic disease
  • acute injury
  • regeneration
  • infectious disease
  • cancer
  • autoimmunity
  • neurodegenerative disease
  • comparative animal models
  • extracellular vesicles
  • liquid biopsy
  • biomarkers

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomedicines
biomedicines
3.9 5.2 2013 15.3 Days CHF 2600 Submit
Cells
cells
5.1 9.9 2012 17.5 Days CHF 2700 Submit
Current Issues in Molecular Biology
cimb
2.8 2.9 1999 16.8 Days CHF 2200 Submit
Genes
genes
2.8 5.2 2010 16.3 Days CHF 2600 Submit
International Journal of Molecular Sciences
ijms
4.9 8.1 2000 18.1 Days CHF 2900 Submit

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Published Papers (15 papers)

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20 pages, 4383 KiB  
Article
Methanolic Extract of Phoenix Dactylifera Confers Protection against Experimental Diabetic Cardiomyopathy through Modulation of Glucolipid Metabolism and Cardiac Remodeling
by Laaraib Nawaz, David J. Grieve, Humaira Muzaffar, Arslan Iftikhar and Haseeb Anwar
Cells 2024, 13(14), 1196; https://doi.org/10.3390/cells13141196 - 15 Jul 2024
Viewed by 397
Abstract
The incidence of cardiovascular disorders is continuously rising, and there are no effective drugs to treat diabetes-associated heart failure. Thus, there is an urgent need to explore alternate approaches, including natural plant extracts, which have been successfully exploited for therapeutic purposes. The current [...] Read more.
The incidence of cardiovascular disorders is continuously rising, and there are no effective drugs to treat diabetes-associated heart failure. Thus, there is an urgent need to explore alternate approaches, including natural plant extracts, which have been successfully exploited for therapeutic purposes. The current study aimed to explore the cardioprotective potential of Phoenix dactylifera (PD) extract in experimental diabetic cardiomyopathy (DCM). Following in vitro phytochemical analyses, Wistar albino rats (N = 16, male; age 2–3 weeks) were fed with a high-fat or standard diet prior to injection of streptozotocin (35 mg/kg i.p.) after 2 months and separation into the following four treatment groups: healthy control, DCM control, DCM metformin (200 mg/kg/day, as the reference control), and DCM PD treatment (5 mg/kg/day). After 25 days, glucolipid and myocardial blood and serum markers were assessed along with histopathology and gene expression of both heart and pancreatic tissues. The PD treatment improved glucolipid balance (FBG 110 ± 5.5 mg/dL; insulin 17 ± 3.4 ng/mL; total cholesterol 75 ± 8.5 mg/dL) and oxidative stress (TOS 50 ± 7.8 H2O2equiv./L) in the DCM rats, which was associated with preserved structural integrity of both the pancreas and heart compared to the DCM control (FBG 301 ± 10 mg/dL; insulin 27 ± 3.4 ng/mL; total cholesterol 126 ± 10 mg/dL; TOS 165 ± 12 H2O2equiv./L). Gene expression analyses revealed that PD treatment upregulated the expression of insulin signaling genes in pancreatic tissue (INS-I 1.69 ± 0.02; INS-II 1.3 ± 0.02) and downregulated profibrotic gene expression in ventricular tissue (TGF-β 1.49 ± 0.04) compared to the DCM control (INS-I 0.6 ± 0.02; INS-II 0.49 ± 0.03; TGF-β 5.7 ± 0.34). Taken together, these data indicate that Phoenix dactylifera may offer cardioprotection in DCM by regulating glucolipid balance and metabolic signaling. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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18 pages, 4617 KiB  
Article
Luteolin-7-O-β-d-Glucuronide Attenuated Cerebral Ischemia/Reperfusion Injury: Involvement of the Blood–Brain Barrier
by Xing Fan, Jintao Song, Shuting Zhang, Lihui Lu, Fang Lin, Yu Chen, Shichang Li, Xinxin Jin and Fang Wang
Biomedicines 2024, 12(6), 1366; https://doi.org/10.3390/biomedicines12061366 - 19 Jun 2024
Viewed by 597
Abstract
Ischemic stroke is a common cerebrovascular disease with high mortality, high morbidity, and high disability. Cerebral ischemia/reperfusion injury seriously affects the quality of life of patients. Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid compound extracted from Ixeris sonchifolia (Bge.) Hance, a Chinese medicinal [...] Read more.
Ischemic stroke is a common cerebrovascular disease with high mortality, high morbidity, and high disability. Cerebral ischemia/reperfusion injury seriously affects the quality of life of patients. Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid compound extracted from Ixeris sonchifolia (Bge.) Hance, a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the protective effect of LGU on cerebral ischemia/reperfusion injury was investigated in an oxygen–glucose deprivation/reoxygenation (OGD/R) neuronal model and a transient middle cerebral artery occlusion (tMCAO) rat model. In in vitro experiments, LGU was found to improve the OGD/R-induced decrease in neuronal viability effectively by the MTT assay. In in vivo experiments, neurological deficit scores, infarction volume rates, and brain water content rates were improved after a single intravenous administration of LGU. These findings suggest that LGU has significant protective effects on cerebral ischemia/reperfusion injury in vitro and in vivo. To further explore the potential mechanism of LGU on cerebral ischemia/reperfusion injury, we performed a series of tests. The results showed that a single administration of LGU decreased the content of EB and S100B and ameliorated the abnormal expression of tight junction proteins ZO-1 and occludin and metalloproteinase MMP-9 in the ischemic cerebral cortex of the tMCAO 24-h injury model. In addition, LGU also improved the tight junction structure between endothelial cells and the degree of basement membrane degradation and reduced the content of TNF-α and IL-1β in the brain tissue. Thereby, LGU attenuated cerebral ischemia/reperfusion injury by improving the permeability of the blood–brain barrier. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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23 pages, 5752 KiB  
Article
A Double-Humanized Mouse Model for Studying Host Gut Microbiome–Immune Interactions in Gulf War Illness
by Dipro Bose, Punnag Saha, Subhajit Roy, Ayushi Trivedi, Madhura More, Nancy Klimas, Ashok Tuteja and Saurabh Chatterjee
Int. J. Mol. Sci. 2024, 25(11), 6093; https://doi.org/10.3390/ijms25116093 - 31 May 2024
Viewed by 547
Abstract
Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery [...] Read more.
Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut–immune interactions in GWI. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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15 pages, 3049 KiB  
Article
Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Protects against Binge Alcohol-Mediated Gut and Brain Injury
by Bipul Ray, Wiramon Rungratanawanich, Karli R. LeFort, Saravana Babu Chidambaram and Byoung-Joon Song
Cells 2024, 13(11), 927; https://doi.org/10.3390/cells13110927 - 28 May 2024
Viewed by 639
Abstract
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and Aldh2-knockout (KO) mice are more susceptible to alcohol-induced tissue damage. However, the underlying mechanisms behind ALDH2-related gut-associated brain damage remain unclear. Age-matched young female Aldh2-KO and C57BL/6J wild-type [...] Read more.
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) metabolizes acetaldehyde to acetate. People with ALDH2 deficiency and Aldh2-knockout (KO) mice are more susceptible to alcohol-induced tissue damage. However, the underlying mechanisms behind ALDH2-related gut-associated brain damage remain unclear. Age-matched young female Aldh2-KO and C57BL/6J wild-type (WT) mice were gavaged with binge alcohol (4 g/kg/dose, three doses) or dextrose (control) at 12 h intervals. Tissues and sera were collected 1 h after the last ethanol dose and evaluated by histological and biochemical analyses of the gut and hippocampus and their extracts. For the mechanistic study, mouse neuroblast Neuro2A cells were exposed to ethanol with or without an Aldh2 inhibitor (Daidzin). Binge alcohol decreased intestinal tight/adherens junction proteins but increased oxidative stress-mediated post-translational modifications (PTMs) and enterocyte apoptosis, leading to elevated gut leakiness and endotoxemia in Aldh2-KO mice compared to corresponding WT mice. Alcohol-exposed Aldh2-KO mice also showed higher levels of hippocampal brain injury, oxidative stress-related PTMs, and neuronal apoptosis than the WT mice. Additionally, alcohol exposure reduced Neuro2A cell viability with elevated oxidative stress-related PTMs and apoptosis, all of which were exacerbated by Aldh2 inhibition. Our results show for the first time that ALDH2 plays a protective role in binge alcohol-induced brain injury partly through the gut–brain axis, suggesting that ALDH2 is a potential target for attenuating alcohol-induced tissue injury. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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11 pages, 1895 KiB  
Communication
Decreased Memory and Learning Ability Mediated by Bmal1/M1 Macrophages/Angptl2/Inflammatory Cytokine Pathway in Mice Exposed to Long-Term Blue Light Irradiation
by Keiichi Hiramoto, Sayaka Kubo, Keiko Tsuji, Daijiro Sugiyama and Hideo Hamano
Curr. Issues Mol. Biol. 2024, 46(5), 4924-4934; https://doi.org/10.3390/cimb46050295 - 18 May 2024
Viewed by 566
Abstract
Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined [...] Read more.
Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined the effects of widespread blue light exposure on the learning and memory abilities of blue light-exposed mice. Ten-week-old male ICR mice were divided into five groups (five mice/group) and irradiated with blue light from a light-emitting diode daily for 6 months. After 6 months of blue light irradiation, mice exhibited a decline in memory and learning abilities, assessed using the Morris water maze and step-through passive avoidance paradigms. Blue light-irradiated mice exhibited a decreased expression of the clock gene brain and muscle arnt-like 1 (Bmal1). The number of microglia and levels of M1 macrophage CC-chemokine receptor 7 and inducible nitric oxide synthase were increased, accompanied by a decrease in M2 macrophage arginase-1 levels. Levels of angiopoietin-like protein 2 and inflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-1β were elevated. Our findings suggest that long-term blue light exposure could reduce Bmal1 expression, activate the M1 macrophage/Angptl2/inflammatory cytokine pathway, induce neurodegeneration, and lead to a decline in memory. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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16 pages, 3262 KiB  
Article
Restraint Stress-Induced Neutrophil Inflammation Contributes to Concurrent Gastrointestinal Injury in Mice
by Rina Munalisa, Te-Sheng Lien, Ping-Yeh Tsai, Der-Shan Sun, Ching-Feng Cheng, Wen-Sheng Wu, Chi-Cheng Li, Chi-Tan Hu, Kuo-Wang Tsai, Yungling Leo Lee, Yu-Chi Chou and Hsin-Hou Chang
Int. J. Mol. Sci. 2024, 25(10), 5261; https://doi.org/10.3390/ijms25105261 - 11 May 2024
Viewed by 1031
Abstract
Psychological stress increases risk of gastrointestinal tract diseases. However, the mechanism behind stress-induced gastrointestinal injury is not well understood. The objective of our study is to elucidate the putative mechanism of stress-induced gastrointestinal injury and develop an intervention strategy. To achieve this, we [...] Read more.
Psychological stress increases risk of gastrointestinal tract diseases. However, the mechanism behind stress-induced gastrointestinal injury is not well understood. The objective of our study is to elucidate the putative mechanism of stress-induced gastrointestinal injury and develop an intervention strategy. To achieve this, we employed the restraint stress mouse model, a well-established method to study the pathophysiological changes associated with psychological stress in mice. By orally administering gut-nonabsorbable Evans blue dye and monitoring its plasma levels, we were able to track the progression of gastrointestinal injury in live mice. Additionally, flow cytometry was utilized to assess the viability, death, and inflammatory status of splenic leukocytes, providing insights into the stress-induced impact on the innate immune system associated with stress-induced gastrointestinal injury. Our findings reveal that neutrophils represent the primary innate immune leukocyte lineage responsible for stress-induced inflammation. Splenic neutrophils exhibited elevated expression levels of the pro-inflammatory cytokine IL-1, cellular reactive oxygen species, mitochondrial burden, and cell death following stress challenge compared to other innate immune cells such as macrophages, monocytes, and dendritic cells. Regulated cell death analysis indicated that NETosis is the predominant stress-induced cell death response among other analyzed regulated cell death pathways. NETosis culminates in the formation and release of neutrophil extracellular traps, which play a crucial role in modulating inflammation by binding to pathogens. Treatment with the NETosis inhibitor GSK484 rescued stress-induced neutrophil extracellular trap release and gastrointestinal injury, highlighting the involvement of neutrophil extracellular traps in stress-induced gastrointestinal inflammation. Our results suggest that neutrophil NETosis could serve as a promising drug target for managing psychological stress-induced gastrointestinal injuries. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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11 pages, 2013 KiB  
Article
Optimizing Embryo Collection for Application of CRISPR/Cas9 System and Generation of Fukutin Knockout Rat Using This Method
by Dong-Won Seol, Byoung-Jin Park, Deog-Bon Koo, Ji-Su Kim, Yong-Hyun Jeon, Jae-Eon Lee, Joon-Suk Park, Hoon Jang and Gabbine Wee
Curr. Issues Mol. Biol. 2024, 46(5), 3752-3762; https://doi.org/10.3390/cimb46050234 - 23 Apr 2024
Viewed by 701
Abstract
Rat animal models are widely used owing to their relatively superior cognitive abilities and higher similarity compared with mouse models to human physiological characteristics. However, their use is limited because of difficulties in establishing embryonic stem cells and performing genetic modifications, and insufficient [...] Read more.
Rat animal models are widely used owing to their relatively superior cognitive abilities and higher similarity compared with mouse models to human physiological characteristics. However, their use is limited because of difficulties in establishing embryonic stem cells and performing genetic modifications, and insufficient embryological research. In this study, we established optimal superovulation and fertilized–egg transfer conditions, including optimal hormone injection concentration (≥150 IU/kg of PMSG and hCG) and culture medium (mR1ECM), to obtain high-quality zygotes and establish in vitro fertilization conditions for rats. Next, sgRNA with optimal targeting activity was selected by performing PCR analysis and the T7E1 assay, and the CRISPR/Cas9 system was used to construct a rat model for muscular dystrophy by inducing a deficiency in the fukutin gene without any off-target effect detected. The production of fukutin knockout rats was phenotypically confirmed by observing a drop-in body weight to one-third of that of the control group. In summary, we succeeded in constructing the first muscular dystrophy disease rat model using the CRISPR/CAS9 system for increasing future prospects of producing various animal disease models and encouraging disease research using rats. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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21 pages, 4072 KiB  
Article
AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes
by Ophélie Vacca, Faouzi Zarrouki, Charlotte Izabelle, Mehdi Belmaati Cherkaoui, Alvaro Rendon, Deniz Dalkara and Cyrille Vaillend
Cells 2024, 13(8), 718; https://doi.org/10.3390/cells13080718 - 20 Apr 2024
Viewed by 1419
Abstract
A deficiency in the shortest dystrophin-gene product, Dp71, is a pivotal aggravating factor for intellectual disabilities in Duchenne muscular dystrophy (DMD). Recent advances in preclinical research have achieved some success in compensating both muscle and brain dysfunctions associated with DMD, notably using exon [...] Read more.
A deficiency in the shortest dystrophin-gene product, Dp71, is a pivotal aggravating factor for intellectual disabilities in Duchenne muscular dystrophy (DMD). Recent advances in preclinical research have achieved some success in compensating both muscle and brain dysfunctions associated with DMD, notably using exon skipping strategies. However, this has not been studied for distal mutations in the DMD gene leading to Dp71 loss. In this study, we aimed to restore brain Dp71 expression in the Dp71-null transgenic mouse using an adeno-associated virus (AAV) administrated either by intracardiac injections at P4 (ICP4) or by bilateral intracerebroventricular (ICV) injections in adults. ICP4 delivery of the AAV9-Dp71 vector enabled the expression of 2 to 14% of brain Dp71, while ICV delivery enabled the overexpression of Dp71 in the hippocampus and cortex of adult mice, with anecdotal expression in the cerebellum. The restoration of Dp71 was mostly located in the glial endfeet that surround capillaries, and it was associated with partial localization of Dp71-associated proteins, α1-syntrophin and AQP4 water channels, suggesting proper restoration of a scaffold of proteins involved in blood–brain barrier function and water homeostasis. However, this did not result in significant improvements in behavioral disturbances displayed by Dp71-null mice. The potential and limitations of this AAV-mediated strategy are discussed. This proof-of-concept study identifies key molecular markers to estimate the efficiencies of Dp71 rescue strategies and opens new avenues for enhancing gene therapy targeting cognitive disorders associated with a subgroup of severely affected DMD patients. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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12 pages, 3156 KiB  
Article
Development and Characterization of a Novel FVB-PrkdcR2140C Mouse Model for Adriamycin-Induced Nephropathy
by Masaki Watanabe, Yuki Ishii, Kazuki Hashimoto, Hayato R. Takimoto and Nobuya Sasaki
Genes 2024, 15(4), 456; https://doi.org/10.3390/genes15040456 - 4 Apr 2024
Viewed by 847
Abstract
The Adriamycin (ADR) nephropathy model, which induces podocyte injury, is limited to certain mouse strains due to genetic susceptibilities, such as the PrkdcR2140C polymorphism. The FVB/N strain without the R2140C mutation resists ADR nephropathy. Meanwhile, a detailed analysis of the progression of [...] Read more.
The Adriamycin (ADR) nephropathy model, which induces podocyte injury, is limited to certain mouse strains due to genetic susceptibilities, such as the PrkdcR2140C polymorphism. The FVB/N strain without the R2140C mutation resists ADR nephropathy. Meanwhile, a detailed analysis of the progression of ADR nephropathy in the FVB/N strain has yet to be conducted. Our research aimed to create a novel mouse model, the FVB-PrkdcR2140C, by introducing PrkdcR2140C into the FVB/NJcl (FVB) strain. Our study showed that FVB-PrkdcR2140C mice developed severe renal damage when exposed to ADR, as evidenced by significant albuminuria and tubular injury, exceeding the levels observed in C57BL/6J (B6)-PrkdcR2140C. This indicates that the FVB/N genetic background, in combination with the R2140C mutation, strongly predisposes mice to ADR nephropathy, highlighting the influence of genetic background on disease susceptibility. Using RNA sequencing and subsequent analysis, we identified several genes whose expression is altered in response to ADR nephropathy. In particular, Mmp7, Mmp10, and Mmp12 were highlighted for their differential expression between strains and their potential role in influencing the severity of kidney damage. Further genetic analysis should lead to identifying ADR nephropathy modifier gene(s), aiding in early diagnosis and providing novel approaches to kidney disease treatment and prevention. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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20 pages, 21642 KiB  
Article
Anatomical Anal Stenosis after PPH: Insights from a Retrospective Study and Rat Model
by Chia-Cheng Wen, Shih-Ming Huang and Yi-Wen Wang
Int. J. Mol. Sci. 2024, 25(6), 3543; https://doi.org/10.3390/ijms25063543 - 21 Mar 2024
Viewed by 919
Abstract
High-grade hemorrhoids are usually recommended to receive operational treatments. However, these traditional surgeries are associated with severe postoperative pain. A procedure for prolapse and hemorrhoids (PPH), a circular staple device, has been developed to improve short-term outcomes, including reducing the severity of postoperative [...] Read more.
High-grade hemorrhoids are usually recommended to receive operational treatments. However, these traditional surgeries are associated with severe postoperative pain. A procedure for prolapse and hemorrhoids (PPH), a circular staple device, has been developed to improve short-term outcomes, including reducing the severity of postoperative pain. PPH, compared to conventional surgery, has been associated with the incidence of anatomical anal stenosis. The causes of stenosis after PPH are not yet clear. We first analyzed the complications of our patients with PPH, and then developed a rat model to verify the tension force of PPH using Hematoxylin-eosin, Masson’s trichrome, immunohistochemistry, and immunofluorescence staining. Our clinical data showed that PPH significantly improved postoperative pain, but that it resulted in higher incidences of complications, including anal stenosis, than hemorrhoidectomy. We simulated the status of PPH and developed a rat model to verify PPH’s tension force, including the scarring area and the deposition of proinflammatory factors, angiogenic factors, and fibrotic factors. The tension wound histological data showed more extensive granulation tissue and inflammatory cell infiltration and a thicker epidermis than the control group on day 12 post-operation and tension treatment. In addition to IL-1β and IL-10 cytokines on day 3 and IL-1β, IL-6, and IL-10 cytokines on day 12 post-operation in the tension group, two angiogenic factors, CD31 and VEGF-A, were found to have a more significant expression on day 7 post-operation in the tension group. The mean scar area was larger and the distribution of fibrotic proteins (collagen 1, α-SMA, CTGF, and MMP2) in the tension group was significantly broader than in the control on day 12 post-operation and tension treatment. Based on the findings of our animal model, the development of a lesser tensile force for PPH to decrease the deposition of proinflammatory factors, angiogenic factors, and fibrotic factors is urgently required. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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15 pages, 1996 KiB  
Article
Therapeutic Effects of a Novel Aptamer on Coronaviral Infection-Induced Lung Injury and Systemic Inflammatory Responses
by Yingchun Wang, Mikael Lindstam, David Hwang, Luiza Jedlina and Mingyao Liu
Cells 2024, 13(5), 422; https://doi.org/10.3390/cells13050422 - 28 Feb 2024
Viewed by 1333
Abstract
Background: Coronaviral infection-induced acute lung injury has become a major threat to public health, especially through the ongoing pandemic of COVID-19. Apta-1 is a newly discovered Aptamer that has anti-inflammatory effects on systemic septic responses. The therapeutic effects of Apta-1 on coronaviral infection-induced [...] Read more.
Background: Coronaviral infection-induced acute lung injury has become a major threat to public health, especially through the ongoing pandemic of COVID-19. Apta-1 is a newly discovered Aptamer that has anti-inflammatory effects on systemic septic responses. The therapeutic effects of Apta-1 on coronaviral infection-induced acute lung injury and systemic responses were evaluated in the present study. Methods: Female A/J mice (at 12–14 weeks of age) were challenged with murine hepatitis virus 1 (MHV-1), a coronavirus, at 5000 PFU intranasally, followed by Apta-1 intravenously administered (100 mg/kg, twice) 1.5 h or 2 days after viral delivery. Animals were sacrificed at Day 2 or Day 4. Lung tissues were examined with H&E, immunohistochemistry staining, and western blotting. RT-qPCR was used for cytokine gene expression. Serum and plasma were collected for laboratory assessments. Results: Apta-1 treatment reduced viral titers, prevented MHV-1-induced reduction of circulating blood volume and hemolysis, reduced alveolar space hemorrhage, and protease-activated receptor 1 (PAR-1) cleavage. Apta-1 treatment also significantly reduced chemokine (MKC, MCP-1, and RANTES) levels, as well as AST, ALT, total bilirubin, and reduced unconjugated bilirubin levels in the serum. Conclusion: Apta-1 showed therapeutic benefits in coronaviral infection-induced hemorrhage and PAR-1 cleavage in the lung. It also has anti-inflammatory effects systemically. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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30 pages, 13237 KiB  
Article
Effects of Paraquat, Dextran Sulfate Sodium, and Irradiation on Behavioral and Cognitive Performance and the Gut Microbiome in A53T and A53T-L444P Mice
by Ariel Chaklai, Abigail O’Neil, Shrey Goel, Nick Margolies, Destine Krenik, Ruby Perez, Kat Kessler, Elizabeth Staltontall, Hong Ki (Eric) Yoon, Montzerrat Pantoja, Keaton Stagaman, Kristin Kasschau, Vivek Unni, Robert Duvoisin, Thomas Sharpton and Jacob Raber
Genes 2024, 15(3), 282; https://doi.org/10.3390/genes15030282 - 23 Feb 2024
Viewed by 1558
Abstract
Heterozygous carriers of the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased risk of developing Parkinson’s disease (PD). The GBA mutations result in elevated alpha synuclein (aSyn) levels. Heterozygous mice carrying one allele with the L444P mutation knocked-into the mouse gene show [...] Read more.
Heterozygous carriers of the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased risk of developing Parkinson’s disease (PD). The GBA mutations result in elevated alpha synuclein (aSyn) levels. Heterozygous mice carrying one allele with the L444P mutation knocked-into the mouse gene show increased aSyn levels and are more sensitive to motor deficits following exposure to the neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) MPTP than wild-type mice. Paraquat (PQ), a herbicide, increases PD risk in most studies. Its effects on the brain involve alterations in the gut microbiome. Exposure to dextran sulfate sodium (DSS), a mouse model of colitis, can be used to determine whether gut microbiome alterations are sufficient to induce PD-relevant phenotypes. We rederived the A53T-L444P and A53T mouse lines to assess whether PQ, PQ in combination with radiation exposure (IR), and DSS have differential effects in A53T and A53T-L444P mice and whether these effects are associated with alterations in the gut microbiome. PQ and PQ + IR have differential effects in A53T and A53T-L444P mice. In contrast, effects of DSS are only seen in A53T-L444P mice. Exposure and genotype modulate the relationship between the gut microbiome and behavioral performance. The gut microbiome may be an important mediator of how environmental exposures or genetic mutations yield behavioral and cognitive impacts. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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0 pages, 2937 KiB  
Article
Frameshift Variant in AMPD2 in Cirneco dell’Etna Dogs with Retinopathy and Tremors
by Leonardo Murgiano, Jessica K. Niggel, Leontine Benedicenti, Matteo Cortellari, Arianna Bionda, Paola Crepaldi, Luigi Liotta, Geoffrey K. Aguirre, William A. Beltran and Gustavo D. Aguirre
Genes 2024, 15(2), 238; https://doi.org/10.3390/genes15020238 - 13 Feb 2024
Viewed by 1469
Abstract
While the manifestations of many inherited retinal disorders are limited to loss of vision, others are part of a syndrome that affects multiple tissues, particularly the nervous system. Most syndromic retinal disorders are thought to be recessively inherited. Two dogs out of a [...] Read more.
While the manifestations of many inherited retinal disorders are limited to loss of vision, others are part of a syndrome that affects multiple tissues, particularly the nervous system. Most syndromic retinal disorders are thought to be recessively inherited. Two dogs out of a litter of Cirneco dell′ Etna dogs, both males, showed signs of retinal degeneration, along with tremors and signs described as either atypical seizures or paroxysmal dyskinesias, while the other two male littermates were normal. We named this oculo-neurological syndrome CONS (Cirneco oculo-neurological syndrome), and undertook homozygosity mapping and whole-genome sequencing to determine its potential genetic etiology. Notably, we detected a 1-bp deletion in chromosome 6 that was predicted to cause a frameshift and premature stop codon within the canine AMPD2 gene, which encodes adenosine monophosphate deaminase, an enzyme that converts adenosine 5′-monophosphate (AMP) to inosine 5’-monophosphate (IMP). Genotyping of the available Cirneco population suggested perfect segregation between cases and controls for the variant. Moreover, this variant was absent in canine genomic databases comprised of thousands of unaffected dogs. The AMPD2 genetic variant we identified in dogs presents with retinal manifestations, adding to the spectrum of neurological manifestations associated with AMPD2 variants in humans. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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20 pages, 3212 KiB  
Article
Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance
by Ayushi Trivedi, Dipro Bose, Punnag Saha, Subhajit Roy, Madhura More, Jonathan Skupsky, Nancy G. Klimas and Saurabh Chatterjee
Cells 2024, 13(1), 56; https://doi.org/10.3390/cells13010056 - 27 Dec 2023
Cited by 1 | Viewed by 1500
Abstract
Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse [...] Read more.
Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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21 pages, 3913 KiB  
Article
Severely Damaged Freeze-Injured Skeletal Muscle Reveals Functional Impairment, Inadequate Repair, and Opportunity for Human Stem Cell Application
by Daniela Fioretti, Mario Ledda, Sandra Iurescia, Raffaella Carletti, Cira Di Gioia, Maria Grazia Lolli, Rodolfo Marchese, Antonella Lisi and Monica Rinaldi
Biomedicines 2024, 12(1), 30; https://doi.org/10.3390/biomedicines12010030 - 21 Dec 2023
Viewed by 1051
Abstract
Background: The regeneration of severe traumatic muscle injuries is an unsolved medical need that is relevant for civilian and military medicine. In this work, we produced a critically sized nonhealing muscle defect in a mouse model to investigate muscle degeneration/healing phases. Materials and [...] Read more.
Background: The regeneration of severe traumatic muscle injuries is an unsolved medical need that is relevant for civilian and military medicine. In this work, we produced a critically sized nonhealing muscle defect in a mouse model to investigate muscle degeneration/healing phases. Materials and methods: We caused a freeze injury (FI) in the biceps femoris of C57BL/6N mice. From day 1 to day 25 post-injury, we conducted histological/morphometric examinations, an analysis of the expression of genes involved in inflammation/regeneration, and an in vivo functional evaluation. Results: We found that FI activates cytosolic DNA sensing and inflammatory responses. Persistent macrophage infiltration, the prolonged expression of eMHC, the presence of centrally nucleated myofibers, and the presence of PAX7+ satellite cells at late time points and with chronic physical impairment indicated inadequate repair. By looking at stem-cell-based therapeutic protocols of muscle repair, we investigated the crosstalk between M1-biased macrophages and human amniotic mesenchymal stem cells (hAMSCs) in vitro. We demonstrated their reciprocal paracrine effects where hAMSCs induced a shift of M1 macrophages into an anti-inflammatory phenotype, and M1 macrophages promoted an increase in the expression of hAMSC immunomodulatory factors. Conclusions: Our findings support the rationale for the future use of our injury model to exploit the full potential of in vivo hAMSC transplantation following severe traumatic injuries. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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