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Seminars in Pediatric Surgery Feb 2018Necrotizing enterocolitis (NEC) remains one of the highest causes of mortality and of acute and long-term morbidity in premature infants. Multiple factors are involved... (Review)
Review
Necrotizing enterocolitis (NEC) remains one of the highest causes of mortality and of acute and long-term morbidity in premature infants. Multiple factors are involved in the pathophysiology of NEC including the immaturity of the immune system and the complex changing composition of the intestinal microbiome. This is compounded by the fact that the premature infant should ideally still be a developing fetus and has an immature intestinal tract. Because these complexities are beyond the scope of studies in single-cell cultures, animal models are absolutely essential to understand the mechanisms involved in the pathophysiology of NEC and the effects of inflammation on the immature intestinal tract. To this end, investigators have utilized many different species (e.g., rats, mice, rabbits, quails, piglets, and non-human primates) and conditions to develop models of NEC. Each animal has distinct advantages and drawbacks related to its preterm viability, body size, genetic variability, and cost. The choice of animal model is strongly influenced by the scientific question being addressed. While no model perfectly mimics human NEC, each has greatly improved our understanding of disease. Examples of recent discoveries in NEC pathogenesis and prevention underscore the importance of continued animal research in NEC.
Topics: Animals; Disease Models, Animal; Enterocolitis, Necrotizing; Mice; Rats; Swine
PubMed: 29275813
DOI: 10.1053/j.sempedsurg.2017.11.006 -
Gut Microbes 2012Necrotizing enterocolitis (NEC) is a common and devastating disease of premature infants. Immaturity of the innate immune system of the gut is central to the... (Review)
Review
Necrotizing enterocolitis (NEC) is a common and devastating disease of premature infants. Immaturity of the innate immune system of the gut is central to the pathogenesis of NEC. Recent studies suggest a key role for Paneth cells in this disease. Addressing basic questions on the development and function of immature Paneth cells may shed light on the puzzling pathophysiology of NEC. Current animal models of NEC are limited in their capacity to answer these questions.
Topics: Animals; Disease Models, Animal; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Intestinal Mucosa; Paneth Cells
PubMed: 22895084
DOI: 10.4161/gmic.21738 -
Frontiers in Physiology 2022Preterm infants are more likely to be born with congenital anomalies than those who are born at full-term. Conversely, neonates born with congenital anomalies are also... (Review)
Review
Preterm infants are more likely to be born with congenital anomalies than those who are born at full-term. Conversely, neonates born with congenital anomalies are also more likely to be born preterm than those without congenital anomalies. Moreover, the comorbid impact of prematurity and congenital anomalies is more than cumulative. Multiple common factors increase the risk of brain injury and neurodevelopmental impairment in both preterm babies and those born with congenital anomalies. These include prolonged hospital length of stay, feeding difficulties, nutritional deficits, pain exposure and administration of medications including sedatives and analgesics. Congenital heart disease provides a well-studied example of the impact of comorbid disease with prematurity. Impaired brain growth and maturity is well described in the third trimester in this population; the immature brain is subsequently more vulnerable to further injury. There is a colinear relationship between degree of prematurity and outcome both in terms of mortality and neurological morbidity. Both prematurity and relative brain immaturity independently increase the risk of subsequent neurodevelopmental impairment in infants with CHD. Non-cardiac surgery also poses a greater risk to preterm infants despite the expectation of normal brain growth. Esophageal atresia, diaphragmatic hernia and abdominal wall defects provide examples of congenital anomalies which have been shown to have poorer neurodevelopmental outcomes in the face of prematurity, with associated increased surgical complexity, higher relative cumulative doses of medications, longer hospital and intensive care stay and increased rates of feeding difficulties, compared with infants who experience either prematurity or congenital anomalies alone.
PubMed: 35846015
DOI: 10.3389/fphys.2022.880891 -
Molecular Metabolism Oct 2022The mechanistic target of rapamycin complex 1 (mTORC1) is a key molecule that links nutrients, hormones, and growth factors to cell growth/function. Our previous studies...
OBJECTIVE
The mechanistic target of rapamycin complex 1 (mTORC1) is a key molecule that links nutrients, hormones, and growth factors to cell growth/function. Our previous studies have shown that mTORC1 is required for β-cell functional maturation and identity maintenance; however, the underlying mechanism is not fully understood. This work aimed to understand the underlying epigenetic mechanisms of mTORC1 in regulating β-cell functional maturation.
METHODS
We performed Microarray, MeDIP-seq and ATAC-seq analysis to explore the abnormal epigenetic regulation in 8-week-old immature βRapKO islets. Moreover, DNMT3A was overexpressed in βRapKO islets by lentivirus, and the transcriptome changes and GSIS function were analyzed.
RESULTS
We identified two major epigenetic silencing mechanisms, DNMT3A-dependent DNA methylation and PRC2-dependent H3K27me3 modification, which are responsible for functional immaturity of Raptor-deficient β-cell. Overexpression of DNMT3A partially reversed the immature transcriptome pattern and restored the impaired GSIS in Raptor-deficient β-cells. Moreover, we found that Raptor directly regulated PRC2/EED and H3K27me3 expression levels, as well as a group of immature genes marked with H3K27me3. Combined with ATAC-seq, MeDIP-seq and ChIP-seq, we identified β-cell immature genes with either DNA methylation and/or H3K27me3 modification.
CONCLUSION
The present study advances our understanding of the nutrient sensor mTORC1, by integrating environmental nutrient supply and epigenetic modification, i.e., DNMT3A-mediated DNA methylation and PRC2-mediated histone methylation in regulating β-cell identity and functional maturation, and therefore may impact the disease risk of type 2 diabetes.
Topics: DNA Methylation; Diabetes Mellitus, Type 2; Epigenesis, Genetic; Histones; Humans; Mechanistic Target of Rapamycin Complex 1
PubMed: 35940555
DOI: 10.1016/j.molmet.2022.101559 -
Developmental Neurobiology Apr 2017Dendrites and spines are the main neuronal structures receiving input from other neurons and glial cells. Dendritic and spine number, size, and morphology are some of... (Review)
Review
Dendrites and spines are the main neuronal structures receiving input from other neurons and glial cells. Dendritic and spine number, size, and morphology are some of the crucial factors determining how signals coming from individual synapses are integrated. Much remains to be understood about the characteristics of neuronal dendrites and dendritic spines in autism and related disorders. Although there have been many studies conducted using autism mouse models, few have been carried out using postmortem human tissue from patients. Available animal models of autism include those generated through genetic modifications and those non-genetic models of the disease. Here, we review how dendrite and spine morphology and number is affected in autism and related neurodevelopmental diseases, both in human, and genetic and non-genetic animal models of autism. Overall, data obtained from human and animal models point to a generalized reduction in the size and number, as well as an alteration of the morphology of dendrites; and an increase in spine densities with immature morphology, indicating a general spine immaturity state in autism. Additional human studies on dendrite and spine number and morphology in postmortem tissue are needed to understand the properties of these structures in the cerebral cortex of patients with autism. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017.
Topics: Animals; Autism Spectrum Disorder; Cerebral Cortex; Dendrites; Dendritic Spines; Disease Models, Animal; Humans
PubMed: 27390186
DOI: 10.1002/dneu.22417 -
Paediatric Anaesthesia Jun 2022Neonatal surgery and concomitant anesthesia coincide with a timeframe of rapid brain development. The speed and complexity of early brain development superimposed on... (Review)
Review
Neonatal surgery and concomitant anesthesia coincide with a timeframe of rapid brain development. The speed and complexity of early brain development superimposed on immature regulatory mechanisms that include incomplete cerebral autoregulation, insufficient free radical scavenging and an immature immune response puts the brain at risk. Brain injury may have long-term consequences for multiple functional domains including cognition, learning skills, and behavior. Neurodevelopmental follow-up studies have noted mild-to-moderate deficits in children who underwent major neonatal surgery and related anesthesia. The present review evaluates neonatal surgery against the background of neurobiological processes that unfold at a pace unparalleled by any other period of human brain development. First, a structured summary of early brain development is provided in order to establish theoretical groundwork. Next, literature on brain injury and neurodevelopmental outcome after neonatal surgery is discussed. Special attention is given to recent findings of structural brain damage reported after neonatal surgery. Notably, high-quality imaging data acquired before surgery are currently lacking. Third, mechanisms of injury are interrogated taking the perspective of early brain development into account. We propose a novel disease model that constitutes a triad of inflammation, vascular immaturity, and neurotoxicity of prolonged exposure to anesthetic drugs. With each of these components exacerbating the other, this amalgam incites the perfect storm, resulting in brain injury. When examining the brain, it seems intuitive to distinguish between neonates (i.e., <60 postconceptional weeks) and more mature infants, multiple and/or prolonged anesthesia exposure and single, short surgery. This review culminates in an outline of anesthetic considerations and future directions that we believe will help move the field forward.
Topics: Anesthesia; Anesthetics; Brain; Brain Injuries; Child; Humans; Infant; Infant, Newborn; Neurotoxicity Syndromes
PubMed: 35266610
DOI: 10.1111/pan.14433 -
Neuroscience and Biobehavioral Reviews Jun 2022Immature motor response inhibition in adolescence is considered contributory to adolescent risk-taking and externalizing behaviors. We review studies reporting... (Review)
Review
Immature motor response inhibition in adolescence is considered contributory to adolescent risk-taking and externalizing behaviors. We review studies reporting age-related variations in motor response inhibition and MRI measurements from typically-developing adolescents. Reviewed studies measured response inhibition using one of three tasks-the Stop Signal Task, Go/No-Go, and Antisaccade Task. Task reliability appears to be particularly strong for the SST. Across tasks and study designs, results indicate that inhibitory control improves markedly through early adolescence. The trajectory of change in later adolescence and into young adulthood (i.e., linear or plateauing) varies depending on the task design. Neuroimaging studies identify adult-like response inhibition networks that are involved in behavioral development. The pros and cons of each task are discussed, including recommendations to guide future studies. Ongoing studies in large longitudinal datasets offer opportunities for further exploration of the shape of change in response inhibition, related neural regions, and associations with other affective and cognitive processes to identify potential impacts of motor response inhibition immaturities or individual differences on adolescent risk-taking behaviors.
Topics: Adolescent; Adult; Humans; Inhibition, Psychological; Longitudinal Studies; Magnetic Resonance Imaging; Reproducibility of Results; Young Adult
PubMed: 35367223
DOI: 10.1016/j.neubiorev.2022.104646 -
Metabolism: Clinical and Experimental Mar 2024Diabetes presents a pressing healthcare crisis, necessitating innovative solutions. Organoid technologies have rapidly advanced, leading to the emergence of... (Review)
Review
Diabetes presents a pressing healthcare crisis, necessitating innovative solutions. Organoid technologies have rapidly advanced, leading to the emergence of bioengineering islet organoids as an unlimited source of insulin-producing cells for treating insulin-dependent diabetes. This advancement surpasses the need for cadaveric islet transplantation. However, clinical translation of this approach faces two major limitations: immature endocrine function and the absence of a perfusable vasculature compared to primary human islets. In this review, we summarize the latest developments in bioengineering functional islet organoids in vitro and promoting vascularization of organoid grafts before and after transplantation. We highlight the crucial roles of the vasculature in ensuring long-term survival, maturation, and functionality of islet organoids. Additionally, we discuss key considerations that must be addressed before clinical translation of islet organoid-based therapy, including functional immaturity, undesired heterogeneity, and potential tumorigenic risks.
Topics: Humans; Organoids; Islets of Langerhans Transplantation; Diabetes Mellitus, Type 1; Bioengineering; Insulins; Islets of Langerhans
PubMed: 38211697
DOI: 10.1016/j.metabol.2024.155786 -
Developmental Neuroscience 2009The immature brain is prone to hypoxic-ischemic encephalopathy and stroke. The incidence of arterial stroke in newborns is similar to that in the elderly. However, the... (Review)
Review
The immature brain is prone to hypoxic-ischemic encephalopathy and stroke. The incidence of arterial stroke in newborns is similar to that in the elderly. However, the pathogenesis of ischemic brain injury is profoundly affected by age at the time of the insult. Necrosis is a dominant type of neuronal cell death in adult brain, whereas widespread neuronal apoptosis is unique for the early postnatal synaptogenesis period. The inflammatory response, in conjunction with excitotoxic and oxidative responses, is the major contributor to ischemic injury in both the immature and adult brain, but there are several areas where these responses diverge. We discuss the contribution of various inflammatory mechanisms to injury and repair after cerebral ischemia in the context of CNS immaturity. In particular, we discuss the role of lower expression of selectins, a more limited leukocyte transmigration, undeveloped complement pathways, a more rapid microglial activation, differences in cytokine and chemokine interplay, and a different threshold to oxidative stress in the immature brain. We also discuss differences in activation of intracellular pathways, especially nuclear factor kappaB and mitogen-activated protein kinases. Finally, we discuss emerging data on both the supportive and adverse roles of inflammation in plasticity and repair after stroke.
Topics: Age Factors; Animals; Brain; Cell Death; Cytokines; Humans; Hypoxia-Ischemia, Brain; Inflammation; Intracellular Signaling Peptides and Proteins; Signal Transduction
PubMed: 19672067
DOI: 10.1159/000232556 -
Frontiers in Pharmacology Nov 2013Adolescence, defined as a transition phase toward autonomy and independence, is a natural time of learning and adjustment, particularly in the setting of long-term goals... (Review)
Review
Adolescence, defined as a transition phase toward autonomy and independence, is a natural time of learning and adjustment, particularly in the setting of long-term goals and personal aspirations. It also is a period of heightened sensation seeking, including risk taking and reckless behaviors, which is a major cause of morbidity and mortality among teenagers. Recent observations suggest that a relative immaturity in frontal cortical neural systems may underlie the adolescent propensity for uninhibited risk taking and hazardous behaviors. However, converging preclinical and clinical studies do not support a simple model of frontal cortical immaturity, and there is substantial evidence that adolescents engage in dangerous activities, including drug abuse, despite knowing and understanding the risks involved. Therefore, a current consensus considers that much brain development during adolescence occurs in brain regions and systems that are critically involved in the perception and evaluation of risk and reward, leading to important changes in social and affective processing. Hence, rather than naive, immature and vulnerable, the adolescent brain, particularly the prefrontal cortex, should be considered as prewired for expecting novel experiences. In this perspective, thrill seeking may not represent a danger but rather a window of opportunities permitting the development of cognitive control through multiple experiences. However, if the maturation of brain systems implicated in self-regulation is contextually dependent, it is important to understand which experiences matter most. In particular, it is essential to unveil the underpinning mechanisms by which recurrent adverse episodes of stress or unrestricted access to drugs can shape the adolescent brain and potentially trigger life-long maladaptive responses.
PubMed: 24348419
DOI: 10.3389/fphar.2013.00118