Bovine Milk Oligosaccharides with Sialyllactose Improves Cognition in Preterm Pigs

Optimal nutrition is important after preterm birth to facilitate normal brain development. Human milk is rich in sialic acid and preterm infants may benefit from supplementing formula with sialyllactose to support neurodevelopment. Using pigs as models, we hypothesized that sialyllactose supplementation improves brain development after preterm birth. Pigs (of either sex) were delivered by cesarean section at 90% gestation and fed a milk diet supplemented with either an oligosaccharide-enriched whey with sialyllactose (n = 20) or lactose (n = 20) for 19 days. Cognitive performance was tested in a spatial T-maze. Brains were collected for ex vivo magnetic resonance imaging (MRI), gene expression, and sialic acid measurements. For reference, term piglets (n = 14) were artificially reared under identical conditions and compared with vaginally born piglets naturally reared by the sow (n = 12). A higher proportion of sialyllactose supplemented preterm pigs reached the T-maze learning criteria relative to control preterm pigs (p < 0.05), and approximated the cognition level of term reference pigs (p < 0.01). Furthermore, supplemented pigs had upregulated genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in hippocampus. Sialyllactose supplementation did not lead to higher levels of sialic acid in the hippocampus or change MRI endpoints. Contrary, these parameters were strongly influenced by postconceptional age and postnatal rearing conditions. In conclusion, oligosaccharide-enriched whey with sialyllactose improved spatial cognition, with effects on hippocampal genes related to sialic acid metabolism, myelination, and ganglioside biosynthesis in preterm pigs. Dietary sialic acid enrichment may improve brain development in infants.

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The neuroanatomy of prematurity: Normal brain development and the impact of preterm birth

Clinical Anatomy ◽

10.1002/ca.22430 ◽

2014 ◽

Vol 28 (2) ◽

pp. 168-183 ◽

Cited By ~ 35

Author(s):

Cynthia Ortinau ◽

Jeffrey Neil

Keyword(s):

Preterm Birth ◽

Brain Development ◽

Normal Brain ◽

The Impact ◽

Normal Brain Development

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Faculty Opinions recommendation of Neuroimaging studies of normal brain development and their relevance for understanding childhood neuropsychiatric disorders.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1128875.585969 ◽

2008 ◽

Author(s):

Daniel Dickstein

Keyword(s):

Brain Development ◽

Neuropsychiatric Disorders ◽

Normal Brain ◽

Normal Brain Development

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Repurposing N,N-Dimethylacetamide (DMA), a Pharmaceutical Excipient, as a Prototype Novel Anti-inflammatory Agent for the Prevention and/or Treatment of Preterm Birth

Current Pharmaceutical Design ◽

10.2174/1381612824666180130121706 ◽

2018 ◽

Vol 24 (9) ◽

pp. 989-992 ◽

Cited By ~ 4

Author(s):

Samir Gorasiya ◽

Juliet Mushi ◽

Ryan Pekson ◽

Sabesan Yoganathan ◽

Sandra E. Reznik

Keyword(s):

Preterm Birth ◽

Ex Vivo ◽

The United States ◽

Occurrence Rate ◽

Pharmaceutical Excipient ◽

Ongoing Work ◽

Exciting Line ◽

Pregnant Mice

Background: Preterm birth (PTB), or birth that occurs before 37 weeks of gestation, accounts for the majority of perinatal morbidity and mortality. As of 2016, PTB has an occurrence rate of 9.6% in the United States and accounts for up to 18 percent of births worldwide. Inflammation has been identified as the most common cause of PTB, but effective pharmacotherapy has yet to be developed to prevent inflammation driven PTB. Our group has discovered that N,N-dimethylacetamide (DMA), a readily available solvent commonly used as a pharmaceutical excipient, rescues lipopolysaccharide (LPS)-induced timed pregnant mice from PTB. Methods: We have used in vivo, ex vivo and in vitro approaches to investigate this compound further. Results: Interestingly, we found that DMA suppresses cytokine secretion by inhibiting nuclear factor-kappa B (NF-κB). In ongoing work in this exciting line of investigation, we are currently investigating structural analogs of DMA, some of them novel, to optimize this approach focused on the inflammation associated with PTB. Conclusion: Successful development of pharmacotherapy for the prevention of PTB rests upon the pursuit of multiple strategies to solve this important clinical challenge.

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Mechanism of NanR gene repression and allosteric induction of bacterial sialic acid metabolism

Nature Communications ◽

10.1038/s41467-021-22253-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Christopher R. Horne ◽

Hariprasad Venugopal ◽

Santosh Panjikar ◽

David M. Wood ◽

Amy Henrickson ◽

...

Keyword(s):

Sialic Acid ◽

Dna Binding ◽

Protein Interactions ◽

Acid Metabolism ◽

Environmental Changes ◽

Dna Interaction ◽

Protein Protein Interactions ◽

Nutrient Source ◽

Cryo Electron Microscopy ◽

Close Proximity

AbstractBacteria respond to environmental changes by inducing transcription of some genes and repressing others. Sialic acids, which coat human cell surfaces, are a nutrient source for pathogenic and commensal bacteria. The Escherichia coli GntR-type transcriptional repressor, NanR, regulates sialic acid metabolism, but the mechanism is unclear. Here, we demonstrate that three NanR dimers bind a (GGTATA)3-repeat operator cooperatively and with high affinity. Single-particle cryo-electron microscopy structures reveal the DNA-binding domain is reorganized to engage DNA, while three dimers assemble in close proximity across the (GGTATA)3-repeat operator. Such an interaction allows cooperative protein-protein interactions between NanR dimers via their N-terminal extensions. The effector, N-acetylneuraminate, binds NanR and attenuates the NanR-DNA interaction. The crystal structure of NanR in complex with N-acetylneuraminate reveals a domain rearrangement upon N-acetylneuraminate binding to lock NanR in a conformation that weakens DNA binding. Our data provide a molecular basis for the regulation of bacterial sialic acid metabolism.

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Sialic acid metabolism in sialuria fibroblasts.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)89468-x ◽

1991 ◽

Vol 266 (12) ◽

pp. 7456-7461

Author(s):

R Seppala ◽

F Tietze ◽

D Krasnewich ◽

P Weiss ◽

G Ashwell ◽

...

Keyword(s):

Sialic Acid ◽

Acid Metabolism

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In utero MRI identifies consequences of early-gestation alcohol drinking on fetal brain development in rhesus macaques

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1919048117 ◽

2020 ◽

Vol 117 (18) ◽

pp. 10035-10044

Author(s):

Xiaojie Wang ◽

Verginia C. Cuzon Carlson ◽

Colin Studholme ◽

Natali Newman ◽

Matthew M. Ford ◽

...

Keyword(s):

White Matter ◽

Brain Development ◽

Ex Vivo ◽

Early Recognition ◽

Brain Mri ◽

Fetal Brain ◽

Fetal Mri ◽

Diffusion Anisotropy ◽

Self Administration ◽

White Matter Tracts

One factor that contributes to the high prevalence of fetal alcohol spectrum disorder (FASD) is binge-like consumption of alcohol before pregnancy awareness. It is known that treatments are more effective with early recognition of FASD. Recent advances in retrospective motion correction for the reconstruction of three-dimensional (3D) fetal brain MRI have led to significant improvements in the quality and resolution of anatomical and diffusion MRI of the fetal brain. Here, a rhesus macaque model of FASD, involving oral self-administration of 1.5 g/kg ethanol per day beginning prior to pregnancy and extending through the first 60 d of a 168-d gestational term, was utilized to determine whether fetal MRI could detect alcohol-induced abnormalities in brain development. This approach revealed differences between ethanol-exposed and control fetuses at gestation day 135 (G135), but not G110 or G85. At G135, ethanol-exposed fetuses had reduced brainstem and cerebellum volume and water diffusion anisotropy in several white matter tracts, compared to controls. Ex vivo electrophysiological recordings performed on fetal brain tissue obtained immediately following MRI demonstrated that the structural abnormalities observed at G135 are of functional significance. Specifically, spontaneous excitatory postsynaptic current amplitudes measured from individual neurons in the primary somatosensory cortex and putamen strongly correlated with diffusion anisotropy in the white matter tracts that connect these structures. These findings demonstrate that exposure to ethanol early in gestation perturbs development of brain regions associated with motor control in a manner that is detectable with fetal MRI.

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