Animal Models and Experimental Medicine最新文献

Background: Elevated intracranial pressure (ICP) occurs in several physiological and pathological conditions, yet long-term sequellae are not common, which implies that blood flow is preserved above ischemic thresholds.

Methods: This pilot study sought to confirm this hypothesis using a closed cranial window model in a rat in which ICP was elevated to 120 mmHg for 12 min, and superficial cortical perfusion was measured by laser Doppler flowmetry and laser speckle flowmetry.

Results: Following a transient increase, cortical blood flow decreased to between 25% and 75% of baseline. These levels correspond to disrupted metabolism and decreased protein synthesis but did not exceed thresholds for electrical signaling or membrane integrity. This may partially explain how some episodes of elevated ICP remain benign.

Conclusion: The closed cranial window model provides a platform for prospective study of physiologic responses to artificially elevated ICP during neurosurgery to promote hemostasis.

Background: Chronic kidney disease (CKD) has a high global prevalence and large unmet need. Central to developing new CKD therapies are in vivo models in CKD. However, next-generation antibody, protein, and gene therapies are highly specific, meaning some do not cross-react with rodent targets. This complicates preclinical development, as established in vivo rodent models cannot be utilized unless tool therapeutics are also developed. Tool compounds can be difficult to develop and, if available, typically have different epitopes, sequences, and/or altered affinity, making it unclear how efficacious the lead therapeutic may be, or what dosing regimen to investigate. To address this, we aimed to develop a nonhuman primate model of CKD.

Methods: In vivo rodent unilateral ureteral obstruction (UUO) models kidney fibrosis and is commonly used due to its rapidity, consistency, and ease. We describe translation of this model to the cynomolgus monkey, specifically optimizing the model duration to allow adequate time for assessment of novel therapeutics prior to the fibrotic plateau.

Results: We demonstrated that disease developed more slowly in cynomolgus monkeys than in rodents post-UUO, with advanced fibrosis developing by 6 weeks. The tubulointerstitial fibrosis in cynomolgus monkeys was more consistent with human obstructive disease than in rodents, having a more aggressive tubular basement expansion and a higher fibroblast infiltration. The fibrosis was also associated with increased transglutaminase activity, consistent with that seen in patients with CKD.

Conclusion: This cynomolgus monkey UUO model can be used to test potential human-specific therapeutics in kidney fibrosis.

Background: Oligoasthenospermia is one of the main causes of male infertility. Researchers usually use chemical drugs to directly damage germ cells to prepare oligoasthenospermia models, which disregards the adhesion and migration between spermatogenic cells and Sertoli cells. TAp73 is a critical regulator of the adhesin of germ cell; thus, we sought to explore a novel oligoasthenospermia model based on TAp73 gene suppression.

Methods: Mice in the Pifithrin-α group were injected intraperitoneally with 2.5 mg/kg Pifithrin-α (TAp73 inhibitor) daily for 30 consecutive days. Reproductive hormone levels and epididymal sperm quality, as well as the network morphology of Sertoli cells were tested.

Results: Sperm density, motility, and the relative protein and mRNA expression of TAp73 and Nectin 2 were obviously decreased in the Pifithrin-α group compared with the normal control group. No significant distinction was observed in the relative mRNA and protein expression of ZO-1. Furthermore, the tight junctions (TJs) and apical ectoplasmic specialization (ES) were destroyed in the Pifithrin-α group.

Conclusion: The above results indicate that we successfully established a new oligoasthenospermia mouse model. This study provides a foundation for further exploration of the roles of TAp73 genes during spermatogenesis and provides new research objects for further oligospermia research and future drug discovery.

Oxygen is one of the important substances for the survival of most life systems on the earth, and plateau and underground burrow systems are two typical hypoxic environments. Small mammals living in hypoxic environments have evolved different adaptation strategies, which include increased oxygen delivery, metabolic regulation of physiological responses and other physiological responses that change tissue oxygen utilization. Multi-omics predictions have also shown that these animals have evolved different adaptations to extreme environments. In particular, vascular endothelial growth factor (VEGF) and erythropoietin (EPO), which have specific functions in the control of O₂ delivery, have evolved adaptively in small mammals in hypoxic environments. Naked mole-rats and blind mole-rats are typical hypoxic model animals as they have some resistance to cancer. This review primarily summarizes the main living environment of hypoxia tolerant small mammals, as well as the changes of phenotype, physiochemical characteristics and gene expression mode of their long-term living in hypoxia environment.

Heart transplantation is a lifesaving procedure, which is limited by the availability of donor hearts. Using hearts from donors after circulatory death, which have sustained global ischemia, requires thorough studies on reliable and reproducible models that developing researchers may not have mastered. By combining the most recent literature and our recommendations based on observations and trials and errors, the methods here detail a sound in vivo heterotopic heart transplantation model for rats in which protective interventions on the ischemic heart can be studied, and thus allowing the scientific community to advance organ preservation research. Knowledge gathered from reproducible animal models allow for successful translation to clinical studies.