Noncommunicable diseases, including cardiovascular disease, diabetes, chronic respiratory disease, and cancer, are the leading cause of death in the world. The cost, both monetary and time, of developing therapies to prevent, treat, or manage these diseases has become unsustainable. A contributing factor is inefficient and ineffective preclinical research, in which the animal models utilized do not replicate the complex physiology that influences disease. An ideal preclinical animal model is one that responds similarly to intrinsic and extrinsic influences, providing high translatability and concordance of preclinical findings to humans. The overwhelming genetic, anatomical, physiological, and pathophysiological similarities to humans make miniature swine an ideal model for preclinical studies of human disease. Additionally, recent development of precision gene-editing tools for creation of novel genetic swine models allows the modeling of highly complex pathophysiology and comorbidities. As such, the utilization of swine models in early research allows for the evaluation of novel drug and technology efficacy while encouraging redesign and refinement before committing to clinical testing. This review highlights the appropriateness of the miniature swine for modeling complex physiologic systems, presenting it as a highly translational preclinical platform to validate efficacy and safety of therapies and devices.
Emerging information indicates that epigenetic modification (i.e. histone code and DNA methylation) may be integral to the maintenance and differentiation of neural stem cells (NSC), but their actual involvements have not yet been illustrated. In this study, we demonstrated the dynamic nature of epigenetic marks during the differentiation of quiescent adult rat NSCs in neurospheres. A subpopulation of OCT4+ NSCs in the neurosphere contained Histone marks, trimethylated Histone 3 on lysine 27 (3me-H3K27), 2me-H3K4, and acetylated H4 (Ac-H4). A major decrease of these marks was found prior to or during differentiation, and was further diminished or reprogrammed in diverse subpopulations of migrated NSCs expressing nestin or β-III-tubulin. The DNA methylation mark 5-methyl-cytosine (5-MeC) and the DNA methyltransferase (DNMT) 1 and 3a expression also correlated to the state of differentiation; they were highly present in undifferentiated NSCs but down-regulated in migrated populations. In contrast, the DNA methyl-CpG-binding protein (MBD1) was low in undifferentiated NSCs in neurospheres, but highly appeared in differentiating NSCs. Furthermore, we found a outward translocation of DNA-methylation marks 5-MeC, DNMT1, DNMT3a, and MBD1 in NSCs as differentiation began and proceeded; the 5-MeC from homogeneous nucleus to peripheral-nucleus, and DMNT1a and 3a from nuclear to cytoplasm, indicating chromatin remodeling. Treatment with DNA a methylation inhibitor, 5-aza-cytidine, altered DNA methylation and disrupted migration as indicated by a reduction of migrated neurons and differentiation. These results indicate that chromatin is dynamically remodeled when NSCs transform from the quiescent state to active growth, and that DNA methylation modification is essential for neural stem cell differentiation.
Neuropathic pain (NP) is a significant and disabling clinical problem with very few therapeutic treatment options available. A major priority is to identify the molecular mechanisms responsible for NP. Although many seemingly relevant pathways have been identified, more research is needed before effective clinical interventions can be produced. Initial insults to the nervous system, such as spinal cord injury (SCI), are often compounded by secondary mechanisms such as inflammation, the immune response, and the changing expression of receptors and ion channels. The consequences of these secondary effects myriad and compound those elicited by the primary injury. Chronic NP syndromes following SCI can greatly complicate the clinical treatment of the primary injury and result in high comorbidity. In this review, we will describe physiological outcomes associated with SCI along with some of the mechanisms known to contribute to chronic NP development.
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