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Cutting Edge: IL-1α and Not IL-1β Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality.
Benjamin JT, Moore DJ, Bennett C, van der Meer R, Royce A, Loveland R, Wynn JL
(2018) J Immunol 201: 2873-2878
MeSH Terms: Animals, Animals, Newborn, Female, Humans, Infant, Newborn, Inflammation, Interleukin-1alpha, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Receptors, Interleukin-1 Type I, Sepsis, Signal Transduction
Show Abstract · Added October 12, 2018
Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.
Copyright © 2018 by The American Association of Immunologists, Inc.
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14 MeSH Terms
Transcriptional profiling of the ductus arteriosus: Comparison of rodent microarrays and human RNA sequencing.
Yarboro MT, Durbin MD, Herington JL, Shelton EL, Zhang T, Ebby CG, Stoller JZ, Clyman RI, Reese J
(2018) Semin Perinatol 42: 212-220
MeSH Terms: Animals, Animals, Newborn, Ductus Arteriosus, Embryo, Mammalian, Gene Expression Profiling, Gene Expression Regulation, Developmental, Genetic Association Studies, Humans, Microarray Analysis, Models, Animal, Rodentia, Sequence Analysis, RNA, Species Specificity, Vascular Patency
Show Abstract · Added November 26, 2018
DA closure is crucial for the transition from fetal to neonatal life. This closure is supported by changes to the DA's signaling and structural properties that distinguish it from neighboring vessels. Examining transcriptional differences between these vessels is key to identifying genes or pathways responsible for DA closure. Several microarray studies have explored the DA transcriptome in animal models but varied experimental designs have led to conflicting results. Thorough transcriptomic analysis of the human DA has yet to be performed. A clear picture of the DA transcriptome is key to guiding future research endeavors, both to allow more targeted treatments in the clinical setting, and to understand the basic biology of DA function. In this review, we use a cross-species cross-platform analysis to consider all available published rodent microarray data and novel human RNAseq data in order to provide high priority candidate genes for consideration in future DA studies.
Copyright © 2018 Elsevier Inc. All rights reserved.
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14 MeSH Terms
A Shared Pattern of β-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis.
Sucre JMS, Deutsch GH, Jetter CS, Ambalavanan N, Benjamin JT, Gleaves LA, Millis BA, Young LR, Blackwell TS, Kropski JA, Guttentag SH
(2018) Am J Pathol 188: 853-862
MeSH Terms: A549 Cells, Adult, Animals, Animals, Newborn, Axin Protein, Bronchopulmonary Dysplasia, Cell Nucleus, Epithelial Cells, Female, Fetus, Humans, Idiopathic Pulmonary Fibrosis, Lung, Mice, Inbred C57BL, Phosphorylation, Pregnancy, Pregnancy Trimester, Second, Protein Processing, Post-Translational, Signal Transduction, Tyrosine, beta Catenin
Show Abstract · Added March 21, 2018
Wnt/β-catenin signaling is necessary for normal lung development, and abnormal Wnt signaling contributes to the pathogenesis of both bronchopulmonary dysplasia (BPD) and idiopathic pulmonary fibrosis (IPF), fibrotic lung diseases that occur during infancy and aging, respectively. Using a library of human normal and diseased human lung samples, we identified a distinct signature of nuclear accumulation of β-catenin phosphorylated at tyrosine 489 and epithelial cell cytosolic localization of β-catenin phosphorylated at tyrosine 654 in early normal lung development and fibrotic lung diseases BPD and IPF. Furthermore, this signature was recapitulated in murine models of BPD and IPF. Image analysis of immunofluorescence colocalization demonstrated a consistent pattern of elevated nuclear phosphorylated β-catenin in the lung epithelium and surrounding mesenchyme in BPD and IPF, closely resembling the pattern observed in 18-week fetal lung. Nuclear β-catenin phosphorylated at tyrosine 489 associated with an increased expression of Wnt target gene AXIN2, suggesting that the observed β-catenin signature is of functional significance during normal development and injury repair. The association of specific modifications of β-catenin during normal lung development and again in response to lung injury supports the widely held concept that repair of lung injury involves the recapitulation of developmental programs. Furthermore, these observations suggest that β-catenin phosphorylation has potential as a therapeutic target for the treatment and prevention of both BPD and IPF.
Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability.
Kropp PA, Dunn JC, Carboneau BA, Stoffers DA, Gannon M
(2018) Am J Physiol Endocrinol Metab 314: E308-E321
MeSH Terms: Adaptation, Physiological, Animals, Animals, Newborn, Cell Differentiation, Cells, Cultured, Diet, High-Fat, Gene Expression Regulation, Developmental, Glucose, Hepatocyte Nuclear Factor 6, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Male, Mice, Mice, Transgenic, Multipotent Stem Cells, Organogenesis, Trans-Activators
Show Abstract · Added April 15, 2019
The transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and onecut1 (Oc1) are coexpressed in multipotent pancreatic progenitors (MPCs), but their expression patterns diverge in hormone-expressing cells, with Oc1 expression being extinguished in the endocrine lineage and Pdx1 being maintained at high levels in β-cells. We previously demonstrated that cooperative function of these two factors in MPCs is necessary for proper specification and differentiation of pancreatic endocrine cells. In those studies, we observed a persistent decrease in expression of the β-cell maturity factor MafA. We therefore hypothesized that Pdx1 and Oc1 cooperativity in MPCs impacts postnatal β-cell maturation and function. Here our model of Pdx1-Oc1 double heterozygosity was used to investigate the impact of haploinsufficiency for both of these factors on postnatal β-cell maturation, function, and adaptability. Examining mice at postnatal day (P) 14, we observed alterations in pancreatic insulin content in both Pdx1 heterozygotes and double heterozygotes. Gene expression analysis at this age revealed significantly decreased expression of many genes important for glucose-stimulated insulin secretion (e.g., Glut2, Pcsk1/2, Abcc8) exclusively in double heterozygotes. Analysis of P14 islets revealed an increase in the number of mixed islets in double heterozygotes. We predicted that double-heterozygous β-cells would have an impaired ability to respond to stress. Indeed, we observed that β-cell proliferation fails to increase in double heterozygotes in response to either high-fat diet or placental lactogen. We thus report here the importance of cooperation between regulatory factors early in development for postnatal islet maturation and adaptability.
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A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus.
Kamitakahara A, Bouyer K, Wang CH, Simerly R
(2018) J Comp Neurol 526: 133-145
MeSH Terms: Age Factors, Agouti-Related Protein, Analysis of Variance, Animals, Animals, Newborn, Arcuate Nucleus of Hypothalamus, Axons, ELAV-Like Protein 3, Estrogen Receptor alpha, Female, Green Fluorescent Proteins, Integrases, Leptin, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropeptide Y, Receptors, Leptin, STAT3 Transcription Factor
Show Abstract · Added April 11, 2019
In the developing hypothalamus, the fat-derived hormone leptin stimulates the growth of axons from the arcuate nucleus of the hypothalamus (ARH) to other regions that control energy balance. These projections are significantly reduced in leptin deficient (Lep ) mice and this phenotype is largely rescued by neonatal leptin treatments. However, treatment of mature Lep mice is ineffective, suggesting that the trophic action of leptin is limited to a developmental critical period. To temporally delineate closure of this critical period for leptin-stimulated growth, we treated Lep mice with exogenous leptin during a variety of discrete time periods, and measured the density of Agouti-Related Peptide (AgRP) containing projections from the ARH to the ventral part of the dorsomedial nucleus of the hypothalamus (DMHv), and to the medial parvocellular part of the paraventricular nucleus (PVHmp). The results indicate that leptin loses its neurotrophic potential at or near postnatal day 28. The duration of leptin exposure appears to be important, with 9- or 11-day treatments found to be more effective than shorter (5-day) treatments. Furthermore, leptin treatment for 9 days or more was sufficient to restore AgRP innervation to both the PVHmp and DMHv in Lep females, but only to the DMHv in Lep males. Together, these findings reveal that the trophic actions of leptin are contingent upon timing and duration of leptin exposure, display both target and sex specificity, and that modulation of leptin-dependent circuit formation by each of these factors may carry enduring consequences for feeding behavior, metabolism, and obesity risk.
© 2017 Wiley Periodicals, Inc.
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Distinct roles for the mTOR pathway in postnatal morphogenesis, maturation and function of pancreatic islets.
Sinagoga KL, Stone WJ, Schiesser JV, Schweitzer JI, Sampson L, Zheng Y, Wells JM
(2017) Development 144: 2402-2414
MeSH Terms: Animals, Animals, Newborn, Cell Aggregation, Islets of Langerhans, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Models, Biological, Morphogenesis, Multiprotein Complexes, Mutation, Signal Transduction, TOR Serine-Threonine Kinases
Show Abstract · Added February 6, 2018
While much is known about the molecular pathways that regulate embryonic development and adult homeostasis of the endocrine pancreas, little is known about what regulates early postnatal development and maturation of islets. Given that birth marks the first exposure to enteral nutrition, we investigated how nutrient-regulated signaling pathways influence postnatal islet development in mice. We performed loss-of-function studies of mechanistic target of rapamycin (mTOR), a highly conserved kinase within a nutrient-sensing pathway known to regulate cellular growth, morphogenesis and metabolism. Deletion of Mtor in pancreatic endocrine cells had no significant effect on their embryonic development. However, within the first 2 weeks after birth, mTOR-deficient islets became dysmorphic, β-cell maturation and function were impaired, and animals lost islet mass. Moreover, we discovered that these distinct functions of mTOR are mediated by separate downstream branches of the pathway, in that mTORC1 (with adaptor protein Raptor) is the main complex mediating the maturation and function of islets, whereas mTORC2 (with adaptor protein Rictor) impacts islet mass and architecture. Taken together, these findings suggest that nutrient sensing may be an essential trigger for postnatal β-cell maturation and islet development.
© 2017. Published by The Company of Biologists Ltd.
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13 MeSH Terms
Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome.
Calhoun JD, Hawkins NA, Zachwieja NJ, Kearney JA
(2017) Epilepsia 58: e111-e115
MeSH Terms: Animals, Animals, Newborn, Calcium Channels, T-Type, Disease Models, Animal, Electroencephalography, Epilepsies, Myoclonic, Fever, Humans, Mice, Mice, Inbred C57BL, Mutation, RNA, Messenger, Video Recording
Show Abstract · Added October 2, 2018
Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage-gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic-clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain-dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T-type calcium channel family, as an epilepsy modifier in the Scn2a transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a Dravet phenotype. Scn1a mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia-induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients.
Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.
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MALDI Imaging Mass Spectrometry as a Lipidomic Approach to Heart Valve Research.
Angel PM, Bayoumi AS, Hinton RB, Ru Su Y, Bichell D, Mayer JE, Scott Baldwin H, Caprioli RM
(2016) J Heart Valve Dis 25: 240-252
MeSH Terms: Age Factors, Algorithms, Animals, Animals, Newborn, Aortic Valve, Aortic Valve Stenosis, Biomarkers, Humans, Lipids, Sheep, Domestic, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added April 17, 2017
BACKGROUND - Valvular disease is characterized in part by lipid deposition, but systematic analysis of the patterns of global lipid expression in healthy and diseased valve tissues are unknown. This is due in part to tissue limitations for lipidomic preparations and technologies for evaluating lipid distribution in tissues. The study aim was to examine the application of matrixassisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to the aortic valve during development and disease, as an approach to detect and map lipids and ultimately better understand valve structure and function.
METHODS - Established MALDI IMS strategies were applied to thin tissue sections of heart valves to map lipids to corresponding morphological features. Healthy prenatal and adult ovine aortic valve tissues were evaluated using the developed techniques. Lipid expression levels were compared between prenatal and adult valves using Wilcoxon rank sum testing and area under the receiver operating curves. A classification algorithm was used to determine distinct lipid signatures in adult extracellular matrix (ECM) substructures, including fibrosa and spongiosa layers. Lipid patterns were examined in heart valve tissue from pediatric patients with congenital aortic valve stenosis (CAVS).
RESULTS - Lipid levels were decreased in adult ovine aortic valves when compared with prenatal valves. Classification algorithms applied to lipid signatures reported distinct lipid signatures mapping to ECM substructures in the adult aortic valve, but could not distinguish amorphous structures at pre-natal day 5. In CAVS, the in-situ lipid aggregation of distinct lipid species showed unique patterning both concurrent and divergent with ECM disarray. Fatty acid content varied between normal and diseased human aortic valves.
CONCLUSIONS - MALDI IMS provides a new and useful approach to evaluate lipid biology in heart valve tissue. These findings define a role for lipid regulation in aortic valve development and demonstrate patterns of lipid deregulation in congenital disease.
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11 MeSH Terms
Sex- and structure-specific differences in antioxidant responses to methylmercury during early development.
Ruszkiewicz JA, Bowman AB, Farina M, Rocha JBT, Aschner M
(2016) Neurotoxicology 56: 118-126
MeSH Terms: Animals, Animals, Newborn, Antioxidants, Brain, Female, Gene Expression Regulation, Developmental, Glutathione, Glutathione Peroxidase, Male, Methylmercury Compounds, Mice, Mice, Inbred C57BL, Pregnancy, Prenatal Exposure Delayed Effects, RNA, Messenger, Sex Characteristics, Thioredoxin-Disulfide Reductase, Thioredoxins
Show Abstract · Added April 26, 2017
Methylmercury (MeHg) is a ubiquitous environmental contaminant and neurotoxin, particularly hazardous to developing and young individuals. MeHg neurotoxicity during early development has been shown to be sex-dependent via disturbances in redox homeostasis, a key event mediating MeHg neurotoxicity. Therefore, we investigated if MeHg-induced changes in key systems of antioxidant defense are sex-dependent. C57BL/6J mice were exposed to MeHg during the gestational and lactational periods, modeling human prenatal and neonatal exposure routes. Dams were exposed to 5ppm MeHg via drinking water from early gestational period until postnatal day 21 (PND21). On PND21 a pair of siblings (a female and a male) from multiple (5-6) litters were euthanized and tissue samples were taken for analysis. Cytoplasmic and nuclear extracts were isolated from fresh cerebrum and cerebellum and used to determine thioredoxin (Trx) and glutathione (GSH) levels, as well as thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) activities. The remaining tissue was used for mRNA analysis. MeHg-induced antioxidant response was not uniform for all the analyzed antioxidant molecules, and sexual dimorphism in response to MeHg treatment was evident for TrxR, Trx and GPx. The pattern of response, namely a decrease in males and an increase in females, may impart differential and sex-specific susceptibility to MeHg. GSH levels were unchanged in MeHg treated animals and irrespective of sex. Trx was reduced only in nuclear extracts from male cerebella, exemplifying a structure-specific response. Results from the gene expression analysis suggest posttranscriptional mechanism of sex-specific regulation of the antioxidant response upon MeHg treatment. The study demonstrates for the first time sex-and structure-specific changes in the response of the thioredoxin system to MeHg neurotoxicity and suggests that these differences in antioxidant responses might impart differential susceptibility to developmental MeHg exposure.
Copyright © 2016 Elsevier B.V. All rights reserved.
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18 MeSH Terms
Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18.
Wynn JL, Wilson CS, Hawiger J, Scumpia PO, Marshall AF, Liu JH, Zharkikh I, Wong HR, Lahni P, Benjamin JT, Plosa EJ, Weitkamp JH, Sherwood ER, Moldawer LL, Ungaro R, Baker HV, Lopez MC, McElroy SJ, Colliou N, Mohamadzadeh M, Moore DJ
(2016) Proc Natl Acad Sci U S A 113: E2627-35
MeSH Terms: Animals, Animals, Newborn, Antibodies, Monoclonal, Female, Interleukin-17, Interleukin-18, Male, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy, Neonatal Sepsis, Survival Rate, Treatment Outcome
Show Abstract · Added April 27, 2016
Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18-null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G(+) myeloid cells, and blocking IL-17A reduced IL-18-potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18-mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis.
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13 MeSH Terms