Animal Models and Experimental Medicine最新文献

Background: Liqoseal consists of a watertight layer of poly(ester)ether urethane and an adhesive layer containing polyethylene glycol-N-hydroxysuccinimide (PEG-NHS). It is designed to prevent cerebrospinal fluid (CSF) leakage after intradural surgery. This study assessed the safety and biodegradability of Liqoseal in a porcine craniotomy model.

Methods: In 32 pigs a craniotomy plus durotomy was performed. In 15 pigs Liqoseal was implanted, in 11 control pigs no sealant was implanted and in 6 control pigs a control dural sealant (Duraseal or Tachosil) was implanted. The safety of Liqoseal was evaluated by clinical, MRI and histological assessment. The degradation of Liqoseal was histologically estimated.

Results: Liqoseal, 2 mm thick before application, did not swell and significantly was at maximum mean thickness of 2.14 (±0.37) mm at one month. The foreign body reaction induced by Liqoseal, Duraseal and Tachosil were comparable. Liqoseal showed no adherence to the arachnoid layer and was completely resorbed between 6 and 12 months postoperatively. In one animal with Liqoseal, an epidural fluid collection containing CSF could not be excluded.

Conclusion: Liqoseal seems to be safe for intracranial use and is biodegradable. The safety and performance in humans needs to be further assessed in clinical trials.

Background: Multiple mitochondrial dysfunction syndromes (MMDS) presents as complex mitochondrial damage, thus impairing a variety of metabolic pathways. Heart dysplasia has been reported in MMDS patients; however, the specific clinical symptoms and pathogenesis remain unclear. More urgently, there is a lack of an animal model to aid research. Therefore, we selected a reported MMDS causal gene, Isca1, and established an animal model of MMDS complicated with cardiac dysplasia.

Methods: The myocardium-specific Isca1 knockout heterozygote (Isca1 HET) rat was obtained by crossing the Isca1 conditional knockout (Isca1 cKO) rat with the α myosin heavy chain Cre (α-MHC-Cre) rat. Cardiac development characteristics were determined by ECG, blood pressure measurement, echocardiography and histopathological analysis. The responsiveness to pathological stimuli were observed through adriamycin treatment. Mitochondria and metabolism disorder were determined by activity analysis of mitochondrial respiratory chain complex and ATP production in myocardium.

Results: ISCA1 expression in myocardium exhibited a semizygous effect. Isca1 HET rats exhibited dilated cardiomyopathy characteristics, including thin-walled ventricles, larger chambers, cardiac dysfunction and myocardium fibrosis. Downregulated ISCA1 led to deteriorating cardiac pathological processes at the global and organizational levels. Meanwhile, HET rats exhibited typical MMDS characteristics, including damaged mitochondrial morphology and enzyme activity for mitochondrial respiratory chain complexes Ⅰ, Ⅱ and Ⅳ, and impaired ATP production.

Conclusion: We have established a rat model of MMDS complicated with cardiomyopathy, it can also be used as model of myocardial energy metabolism dysfunction and mitochondrial cardiomyopathy. This model can be applied to the study of the mechanism of energy metabolism in cardiovascular diseases, as well as research and development of drugs.

We emphasize the importance of studying the primate brain in cognitive neuroscience and suggest a new mind-set in primate experimentation within the boundaries of animal welfare regulations. Specifically, we list the advantages of investigating both genes and neural mechanisms and processes in the emergence of behavioral and cognitive functions, and propose the establishment of an open field of primate research. The latter may be conducted by implementing and harmonizing experimental practices with ethical guidelines that regulate (1) management of natural parks with free-moving populations of target nonhuman primates, (2) establishment of indoor-outdoor labs for both system genetics and neuroscience investigations, and (3) hotel space and technologies which remotely collect and dislocate information regarding primates geographically located elsewhere.

Oxygen plays a pivotal role in the metabolism and activities of mammals. However, oxygen is restricted in some environments-subterranean burrow systems or habitats at high altitude or deep in the ocean-and this could exert hypoxic stresses such as oxidative damage on organisms living in these environments. In order to cope with these stresses, organisms have evolved specific strategies to adapt to hypoxia, including changes in physiology, gene expression regulation, and genetic mutations. Here, we review how mammals have adapted to the three high-altitude plateaus of the world, the limited oxygen dissolved in deep water habitats, and underground tunnels, with the aim of better understanding the adaptation of mammals to hypoxia.

Background: Hematopoietic stem cells (HSC) maintain the hematopoietic system homeostasis through self-renewal and multilineage differentiation potential. HSC are regulated by the microenvironment, cytokine signaling, and transcription factors. Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence, proliferation, and division. However, the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified. Lipoprotein lipase (LPL) is an essential enzyme in the anabolism and catabolism of very low-density lipoprotein, chylomicrons, and triglyceride-rich lipoproteins.

Methods: The percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence-activated cell sorting (FACS). The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis. The changes in LPL^+/- HSC microenvironment were detected by transplantation assays using red fluorescent protein (RFP) transgenic mice.

Results: To explore the function of LPL in HSC regulation, heterozygous LPL-knockout mice (LPL^+/-) were established and analyzed by FACS. LPL^+/- mice displayed decreased hematopoietic stem/progenitor cell compartments. In vitro single-cell clonogenic assays and cell-cycle assays using FACS promoted the cell cycle and increased proliferation ability. qPCR analysis showed the expression of p57^KIP2 and p21^WAF1/CIP1 in LPL^+/- mice was upregulated.

Conclusions: LPL^+/- mice exhibited HSC compartment impairment due to promotion of HSC proliferation, without any effects on the bone marrow (BM) microenvironment.

The cornea is an avascular, transparent tissue that is essential for visual function. Any disturbance to the corneal transparency will result in a severe vision loss. Due to the avascular nature, the cornea acquires most of the oxygen supply directly or indirectly from the atmosphere. Corneal tissue hypoxia has been noticed to influence the structure and function of the cornea for decades. The etiology of hypoxia of the cornea is distinct from the rest of the body, mainly due to the separation of cornea from the atmosphere, such as prolonged contact lens wearing or closed eyes. Corneal hypoxia can also be found in corneal inflammation and injury when a higher oxygen requirement exceeds the oxygen supply. Systemic hypoxic state during lung diseases or high altitude also leads to corneal hypoxia when a second oxygen consumption route from aqueous humor gets blocked. Hypoxia affects the cornea in multiple aspects, including disturbance of the epithelium barrier function, corneal edema due to endothelial dysfunction and metabolism changes in the stroma, and thinning of corneal stroma. Cornea has also evolved mechanisms to adapt to the hypoxic state initiated by the activation of hypoxia inducible factor (HIF). The aim of this review is to introduce the pathology of cornea under hypoxia and the mechanism of hypoxia adaptation, to discuss the current animal models used in this field, and future research directions.

The kidneys are a vital organ that is vulnerable to both acute kidney injury (AKI) and chronic kidney disease (CKD) which can be caused by numerous risk factors such as ischemia, sepsis, drug toxicity and drug overdose, exposure to heavy metals, and diabetes. In spite of the advances in our understanding of the pathogenesis of AKI and CKD as well AKI transition to CKD, there is still no available therapeutics that can be used to combat kidney disease effectively, highlighting an urgent need to further study the pathological mechanisms underlying AKI, CKD, and AKI progression to CKD. In this regard, animal models of kidney disease are indispensable. This article reviews a widely used animal model of kidney disease, which is induced by folic acid (FA). While a low dose of FA is nutritionally beneficial, a high dose of FA is very toxic to the kidneys. Following a brief description of the procedure for disease induction by FA, major mechanisms of FA-induced kidney injury are then reviewed, including oxidative stress, mitochondrial abnormalities such as impaired bioenergetics and mitophagy, ferroptosis, pyroptosis, and increased expression of fibroblast growth factor 23 (FGF23). Finally, application of this FA-induced kidney disease model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed. Given that this animal model is simple to create and is reproducible, it should remain useful for both studying the pathological mechanisms of kidney disease and identifying therapeutic targets to fight kidney disease.

Objective/background: Proliferation is a widely recognized trigger for pulmonary hypertension (PH), a life-threatening, progressive disorder of pulmonary blood vessels. This study was aimed to identify some proliferation associated genes/targets for better comprehension of PH pathogenesis.

Methods: Human pulmonary arterial smooth muscle cells (hPASMCs) were cultured in the presence or absence of human recombinant platelet derived growth factor (rhPDGF)-BB. Cells were collected for metabolomics or transcriptomics study. Gene profiling of lungs of PH rats after hypoxia exposure or of PH patients were retrieved from GEO database.

Results: 90 metabolites (VIP score >1, fold change >2 or <0.5 and p < .05) and 2701 unique metabolism associated genes (MAGs) were identified in rhPDGF-BB treated hPASMCs compared to control cells. In addition, 1151 differentially expressed genes (313 upregulated and 838 downregulated) were identified in rhPDGF-BB treated hPASMCs compared to control cells (fold change >2 or <0.5 and p < .05). 152 differentially expressed MAGs were then determined, out of which 9 hub genes (IL6, CXCL8, CCL2, CXCR4, CCND1, PLAUR, PLAU, HBEGF and F3) were defined as core proliferation associated hub genes in protein proten interaction analysis. In addition, the hub gene-based LASSO model can predict the occurrence of PH (AUC = 0.88). The expression of CXCR4, as one of the hub genes, was positively correlated to immune cell infiltrates.

Conclusion: Our findings revealed some key proliferation associated genes in PH, which provide the crucial information concerning complex metabolic reprogramming and inflammatory modulation in response to proliferation signals and might offer therapeutic gains for PH.

Background: Wound healing can result in various outcomes, including hypertrophic scar (HTS). Pigs serve as models to study wound healing as their skin shares physiologic similarity with humans. Yorkshire (Yk) and Duroc (Dc) pigs have been used to mimic normal and abnormal wound healing, respectively. The reason behind this differential healing phenotype was explored here.

Methods: Excisional wounds were made on Dc and Yk pigs and were sampled and imaged for 98 days. PCR arrays were used to determine differential gene expression. Vancouver Scar Scale (VSS) scores were given. Re-epithelialization was analyzed. H&E, Mason's trichrome, and immunostains were used to determine cellularity, collagen content, and blood vessel density, respectively.

Results: Yk wounds heal to a "port wine" HTS, resembling scarring in Fitzpatrick skin types (FST) I-III. Dc wounds heal to a dyspigmented, non-pliable HTS, resembling scarring in FST IV-VI. Gene expression during wound healing was differentially regulated versus uninjured skin in 40/80 genes, 15 of which differed between breeds. Yk scars had a higher VSS score at all time points. Yk and Dc wounds had equivalent re-epithelialization, collagen disorganization, and blood vessel density.

Conclusions: Our findings demonstrate that Dc and Yk pigs can produce HTS. Wound creation and healing were consistent among breeds, and differences in gene expression were not sufficient to explain differences in resulting scar phenotype. Both pig breeds should be used in animal models to investigate novel therapeutics to provide insight into a treatment's effectiveness on various skin types.