bims-medebr 2022-09-25 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–09–25
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

The contribution of astrocytes to obesity-associated metabolic disturbances.
Potential new roles for glycogen in epilepsy.
A Role for PGC-1a in the Control of Abnormal Mitochondrial Dynamics in Alzheimer's Disease.
Early-life stress and dietary fatty acids impact the brain lipid/oxylipin profile into adulthood, basally and in response to LPS.
L-Ornithine L-Aspartate Restores Mitochondrial Function and Modulates Intracellular Calcium Homeostasis in Parkinson's Disease Models.
Editorial: Changes in metabolic processes affecting brain development.
Assay of Monoacylglycerol Lipase Activity.
Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway-mediated antioxidant defense in a mouse model of cardiac arrest.
Quantitation of Lactate in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray-Tandem Mass Spectrometry.
Resveratrol and Some of Its Derivatives as Promising Prophylactic Treatments for Neonatal Hypoxia-Ischemia.
Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism.
Serum Phospholipid Profile Changes in Gaucher Disease and Parkinson's Disease.
Olive- and Coconut-Oil-Enriched Diets Decreased Secondary Bile Acids and Regulated Metabolic and Transcriptomic Markers of Brain Injury in the Frontal Cortexes of NAFLD Pigs.
Treatment with THI, an inhibitor of Sphingosine-1-phosphate Lyase (SGPL1), modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease.
The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases.
Tandem Mass Spectrometry for the Analysis of Plasma/Serum Acylcarnitines for the Diagnosis of Certain Organic Acidurias and Fatty Acid Oxidation Disorders.
Phosphatidylethanolamine N-Methyltransferase Knockout Modulates Metabolic Changes in Aging Mice.
Associations of the Lipidome with Ageing, Cognitive Decline and Exercise Behaviours.
N-acetylcysteine treatment mitigates loss of cortical parvalbumin-positive interneuron and perineuronal net integrity resulting from persistent oxidative stress in a rat TBI model.
Alteration of Fatty Acid Profile in Fragile X Syndrome.
Incidence and Risk Factors for Glucose Disturbances in Premature Infants.

J Biomed Res. 2022 Aug 28. 1-13

The contribution of astrocytes to obesity-associated metabolic disturbances.

Marta Obara-Michlewska.

  Obesity is a worldwide health, economic and social concern, despite efforts made to counteract the spreading wave of eating and nourishment-associated disorders. The review aims to show how the glial cells, astrocytes, contribute to the central regulation of appetite and energy metabolism. The hypothalamus is the brain center responsible for nutrients and nutritional hormone sensing, signal processing, and execution of metabolic and behavioral responses, directed at sustaining energy homeostasis. The astrocytes are endowed with receptors, transporters and enzymatic machinery responsible for glucose, lactate, fatty acids, ketone bodies, as well as leptin or ghrelin transport and metabolism, and that render them supporters and partners for neurons in governing the brain and body energy intake and expenditure. However, the role of astrocytes associated with brain energy metabolism reaches far beyond simple fuel contingent-they contribute to cognitive performance. The cognitive decline which often accompanies high fat- and/or high-calorie diets and correlates with neuroinflammation and astrogliosis, is a major concern. The last two decades of research enabled us to acknowledge the astroglia in obesity-associated dysfunctions and to investigate astrocytes as contributors to the pathology, as well as targets for therapy.

Keywords:  astrocytes; astrocytosis; brain energy metabolism; hypothalamic inflammation; obesity

DOI:  https://doi.org/10.7555/JBR.36.20200020
Epilepsia. 2022 Sep 19.

Potential new roles for glycogen in epilepsy.

Gerald A Dienel, Lisa Gillinder, Aileen McGonigal, Karin Borges.

  Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue, often show low signals with 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in many epileptic patients, even when there are no radiologically detectable structural abnormalities. Low FDG-PET signals are thought to reflect glucose hypometabolism. Here we review knowledge about metabolism of glucose and glycogen and oxidative stress in people with epilepsy and acute and chronic rodent seizure models. Interictal brain glucose levels are normal and do not cause apparent glucose hypometabolism that remains unexplained. During seizures, high amounts of fuel are needed to satisfy the energy demands. Astrocytes consume glycogen as an additional emergency fuel to supplement glucose during high metabolic demand, such as during brain stimulation, stress, and seizures. In rodents, brain glycogen levels drop during induced seizures and increase to higher levels thereafter. Interictally, in people with epilepsy and chronic epilepsy models, normal glucose but high glycogen levels have been found in the presumed brain areas involved in seizure generation. We present our new hypothesis that as an adaptive response to repeated episodes of high metabolic demand, high interictal glycogen levels in epileptogenic brain areas are used to support energy metabolism and potentially interictal neuronal activity. Glycogenolysis, which can be triggered by stress or oxidative stress, leads to decreased utilisation of plasma glucose in epileptogenic brain areas resulting in low FDG signals that are related to functional changes underlying seizure onset and propagation. This is (partially) reversible after successful surgery. Last, we propose that potential interictal glycogen depletion in epileptogenic and surrounding areas may cause energy shortages in astrocytes, which may impair potassium buffering and contribute to seizure generation. Based on these hypotheses, auxiliary fuels or treatments that support glycogen metabolism may be useful to treat epilepsy.

Keywords:  FDG-PET; glucose utilization; glycogen; interictal epileptic hyperactivity

DOI:  https://doi.org/10.1111/epi.17412
Cells. 2022 Sep 13. pii: 2849. [Epub ahead of print]11(18):

A Role for PGC-1a in the Control of Abnormal Mitochondrial Dynamics in Alzheimer's Disease.

Jia Wang, Wen-Jun Liu, Hou-Zhen Shi, Hong-Ru Zhai, Jin-Jun Qian, Wei-Ning Zhang.

  Emerging evidence suggests that the proper control of mitochondrial dynamics provides a window for therapeutic intervention for Alzheimer's disease (AD) progression. The transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1 (PGC-1a) has been shown to regulate mitochondrial biogenesis in neurons. Thus far, the roles of PGC-1a in Alzheimer's disease and its potential value for restoring mitochondrial dysfunction remain largely unknown. In the present study, we explored the impacts of PGC-1a on AD pathology and neurobehavioral dysfunction and its potential mechanisms with a particular focus on mitochondrial dynamics. Paralleling AD-related pathological deposits, neuronal apoptosis, abnormal mitochondrial dynamics and lowered membrane potential, a remarkable reduction in the expression of PGC-1a was shown in the cortex of APP/PS1 mice at 6 months of age. By infusing AAV-Ppargc1α into the lateral parietal association (LPtA) cortex of the APP/PS1 brain, we found that PGC-1a ameliorated AD-like behavioral abnormalities, such as deficits in spatial reference memory, working memory and sensorimotor gating. Notably, overexpressed PGC-1a in LPtA rescued mitochondrial swelling and damage in neurons, likely through correcting the altered balance in mitochondrial fission-fusion and its abnormal distribution. Our findings support the notion that abnormal mitochondrial dynamics is likely an important mechanism that leading to mitochondrial dysfunction and AD-related pathological and cognitive impairments, and they indicate the potential value of PGC-1a for restoring mitochondrial dynamics as an innovative therapeutic target for AD.

Keywords:  Alzheimer’s disease; PGC-1a; mitochondrial distribution; mitochondrial dynamics; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/cells11182849
Front Immunol. 2022 ;13 967437

Early-life stress and dietary fatty acids impact the brain lipid/oxylipin profile into adulthood, basally and in response to LPS.

Kitty Reemst, Jelle Y Broos, Maralinde R Abbink, Chiara Cimetti, Martin Giera, Gijs Kooij, Aniko Korosi.

  Brain lipid dysregulation is a hallmark of depression and Alzheimer's disease, also marked by chronic inflammation. Early-life stress (ELS) and dietary intake of polyunsaturated fatty acids (PUFAs) are risk factors for these pathologies and are known to impact inflammatory processes. However, if these early-life factors alter brain lipid homeostasis on the long-term and thereby contribute to this risk remains to be elucidated. We have recently shown that an early diet enriched in omega(ω)-3 PUFAs protected against the long-term negative effects of ELS on cognition and neuroinflammation. Here, we aim to understand if modulation of brain lipid and oxylipin profiles contributes to the detrimental effects of ELS and the protective ones of the diet. We therefore studied if and how ELS and early dietary PUFAs modulate the brain lipid and oxylipin profile, basally as well as in response to an inflammatory challenge, to unmask possible latent effects. Male mice were exposed to ELS via the limited bedding and nesting paradigm, received an early diet with high or low ω6/ω3 ratio (HRD and LRD) and were injected with saline or lipopolysaccharide (LPS) in adulthood. Twenty-four hours later plasma cytokines (Multiplex) and hypothalamic lipids and oxylipins (liquid chromatography tandem mass spectrometry) were measured. ELS exacerbated the LPS-induced increase in IL-6, CXCL1 and CCL2. Both ELS and diet affected the lipid/oxylipin profile long-term. For example, ELS increased diacylglycerol and LRD reduced triacylglycerol, free fatty acids and ceramides. Importantly, the ELS-induced alterations were strongly influenced by the early diet. For example, the ELS-induced decrease in eicosapentaenoic acid was reversed when fed LRD. Similarly, the majority of the LPS-induced alterations were distinct for control and ELS exposed mice and unique for mice fed with LRD or HRD. LPS decreased ceramides and lysophosphotidylcholine, increased hexosylceramides and prostaglandin E2, reduced triacylglycerol species and ω6-derived oxylipins only in mice fed LRD and ELS reduced the LPS-induced increase in phosphatidylcholine. These data give further insights into the alterations in brain lipids and oxylipins that might contribute to the detrimental effects of ELS, to the protective ones of LRD and the possible early-origin of brain lipid dyshomeostasis characterizing ELS-related psychopathologies.

Keywords:  LPS; Oxylipin; PUFA; dietary intervention; early-life stress; lipidomics

DOI:  https://doi.org/10.3389/fimmu.2022.967437
Cells. 2022 Sep 17. pii: 2909. [Epub ahead of print]11(18):

L-Ornithine L-Aspartate Restores Mitochondrial Function and Modulates Intracellular Calcium Homeostasis in Parkinson's Disease Models.

Maria Josè Sisalli, Salvatore Della Notte, Agnese Secondo, Carmelo Ventra, Lucio Annunziato, Antonella Scorziello.

  The altered crosstalk between mitochondrial dysfunction, intracellular Ca2+ homeostasis, and oxidative stress has a central role in the dopaminergic neurodegeneration. In the present study, we investigated the hypothesis that pharmacological strategies able to improve mitochondrial functions might prevent neuronal dysfunction in in vitro models of Parkinson's disease. To this aim, the attention was focused on the amino acid ornithine due to its ability to cross the blood-brain barrier, to selectively reach and penetrate the mitochondria through the ornithine transporter 1, and to control mitochondrial function. To pursue this issue, experiments were performed in human neuroblastoma cells SH-SY5Y treated with rotenone and 6-hydroxydopamine to investigate the pharmacological profile of the compound L-Ornithine-L-Aspartate (LOLA) as a new potential therapeutic strategy to prevent dopaminergic neurons' death. In these models, confocal microscopy experiments with fluorescent dyes measuring mitochondrial calcium content, mitochondrial membrane potential, and mitochondrial ROS production, demonstrated that LOLA improved mitochondrial functions. Moreover, by increasing NCXs expression and activity, LOLA also reduced cytosolic [Ca2+] thanks to its ability to modulate NO production. Collectively, these results indicate that LOLA, by interfering with those mitochondrial mechanisms related to ROS and RNS production, promotes mitochondrial functional recovery, thus confirming the tight relationship existing between cytosolic ionic homeostasis and cellular metabolism depending on the type of insult applied.

Keywords:  NO; Parkinson’s disease; calcium homeostasis; mitochondria; ornithine; sodium-calcium-exchangers

DOI:  https://doi.org/10.3390/cells11182909
Front Neurosci. 2022 ;16 1002010

Editorial: Changes in metabolic processes affecting brain development.

Gregory W Kirschen, Shaoyu Ge.



Keywords:  TORCH; brain organoids; gut microbiome; neurodevelopment; oligodendrocytes; one carbon metabolism; short chain fatty acids

DOI:  https://doi.org/10.3389/fnins.2022.1002010
Methods Mol Biol. 2023 ;2576 285-297

Assay of Monoacylglycerol Lipase Activity.

Kwang-Mook Jung, Daniele Piomelli.

  Monoacylglycerol lipase (MGL/MAGL/MGLL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). 2-AG is the most abundant endogenous lipid agonists for cannabinoid receptors in the brain and elsewhere in the body. In the central nervous system (CNS), MGL is localized to presynaptic nerve terminals of both excitatory and inhibitory synapses, where it controls the regulatory actions of 2-AG on synaptic transmission and plasticity. In this chapter, we describe an in vitro method to assess MGL activity by liquid chromatography/mass spectrometry (LC/MS)-based quantitation of its reaction product. The method may be used to determine basal or altered MGL activity in cells or tissues after pharmacological, genetic, or biological interventions. In addition, the assay can be used for MGL inhibitor screening using purified recombinant enzyme or MGL-overexpressing cells.

Keywords:  2-arachidonoyl-sn-glycerol (2-AG); Arachidonic acid; Enzyme assay; Liquid chromatography/mass spectrometry (LC/MS); Monoacylglycerol lipase (MGL/MAGL)

DOI:  https://doi.org/10.1007/978-1-0716-2728-0_24
Nutrition. 2022 Aug 12. pii: S0899-9007(22)00227-1. [Epub ahead of print]103-104 111814

Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway-mediated antioxidant defense in a mouse model of cardiac arrest.

Fei Peng, Yu-Han Zhang, Lu Zhang, Man Yang, Chan Chen, Hai Yu, Tao Li.

   OBJECTIVE: The aim of this study was to investigate the effect of the ketogenic diet (KD) on post-cardiac arrest brain injury in a mouse model of cardiac arrest and cardiopulmonary resuscitation.
METHODS: Mice were fed a KD for 4 wk and then subjected to cardiac arrest and cardiopulmonary resuscitation. The HT22 cells after β-hydroxybutyrate (β-OHB) treatment were exposed to oxygen-glucose deprivation/reoxygenation. Survival and neurologic function were measured after return of spontaneous circulation. Positron emission tomography/computed tomography scanning, 13C-magnetic resonance spectroscopy analysis, and seahorse assay were performed to explore the mechanism underlying the phenotype.
RESULTS: Results of this study demonstrated that KD improved neurologic function and reduced apoptotic neurons in cardiac arrest and cardiopulmonary resuscitation mice. With no alteration of glucose uptake, KD suppressed glucose oxidation in mouse brain. Consistently, the glycolytic capacity of the HT22 cells was also downregulated by β-OHB treatment. Moreover, KD increased nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate and reduced glutathione/oxidized glutathione couples and reduced reactive oxygen species in the brain, probably due to activation of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway. Pharmacologic inhibition of pentose phosphate pathway totally abolished the influence of β-OHB on glycolysis, and post-oxygen-glucose deprivation/reoxygenation cell viability and reactive oxygen species production in HT22 cells.
CONCLUSION: KD improved survival and attenuated post-cardiac arrest brain injury, which was mediated by upregulation of pentose phosphate pathway and related antioxidant defense system.

Keywords:  Cardiac arrest; Glucose metabolism; Ketogenic diet; Pentose phosphate pathway; Post-cardiac arrest brain injury

DOI:  https://doi.org/10.1016/j.nut.2022.111814
Methods Mol Biol. 2022 ;2546 253-260

Quantitation of Lactate in Cerebrospinal Fluid Using Liquid Chromatography-Electrospray-Tandem Mass Spectrometry.

Brandi Wasek, Erland Arning.

  We describe a simple stable isotope dilution method for accurate and precise measurement of cerebrospinal fluid (CSF) lactate as a clinical diagnostic test. Lactate is produced from cellular metabolism, primarily in muscle cells, and provides a source of energy especially during instances of low oxygen levels. Measurement of lactate in CSF provides diagnostic information regarding the body's oxidative metabolism including diagnosis of lactate acidosis, aiding in the diagnosis of blood-brain barrier glucose transporter defect and differentiation between bacterial and viral meningitis. Determination of lactate in CSF (20 μL) was performed utilizing high-performance liquid chromatography coupled with electrospray positive ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Lactate in CSF is determined by a 1:10 dilution with internal standard (sodium lacate-d3) and injected directly onto the HPLC-ESI-MS/MS system. Each assay is quantified using a six-point standard curve (0.625-20 mM) and has an analytical measurement range of 0.3-20 mM.

Keywords:  Glucose transporter defect; Lactate; Lactate acidosis; Mass spectrometry

DOI:  https://doi.org/10.1007/978-1-0716-2565-1_23
Nutrients. 2022 Sep 14. pii: 3793. [Epub ahead of print]14(18):

Resveratrol and Some of Its Derivatives as Promising Prophylactic Treatments for Neonatal Hypoxia-Ischemia.

Hélène Roumes, Pierre Goudeneche, Luc Pellerin, Anne-Karine Bouzier-Sore.

  Due to the rate of occurrence of neonatal hypoxia-ischemia, its neuronal sequelae, and the lack of effective therapies, the development of new neuroprotective strategies is required. Polyphenols (including resveratrol) are molecules whose anti-apoptotic, anti-inflammatory, and anti-oxidative properties could be effective against the damage induced by neonatal hypoxia-ischemia. In this review article, very recent data concerning the neuroprotective role of polyphenols and the mechanisms at play are detailed, including a boost in brain energy metabolism. The results obtained with innovative approaches, such as maternal supplementation at nutritional doses, suggest that polyphenols could be a promising prophylactic treatment for neonatal hypoxia-ischemia.

Keywords:  neonatal hypoxia-ischemia; neuroprotection; polyphenols

DOI:  https://doi.org/10.3390/nu14183793
Biomolecules. 2022 Aug 27. pii: 1189. [Epub ahead of print]12(9):

Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism.

Abhijit Das, Gregory Gauthier-Coles, Stefan Bröer, Caroline D Rae.

  The cerebellum, or "little brain", is often overlooked in studies of brain metabolism in favour of the cortex. Despite this, anomalies in cerebellar amino acid homeostasis in a range of disorders have been reported. Amino acid homeostasis is central to metabolism, providing recycling of carbon backbones and ammonia between cell types. Here, we examined the role of cerebellar amino acid transporters in the cycling of glutamine and alanine in guinea pig cerebellar slices by inhibiting amino acid transporters and examining the resultant metabolism of [1-13C]d-glucose and [1,2-13C]acetate by NMR spectroscopy and LCMS. While the lack of specific inhibitors of each transporter makes interpretation difficult, by viewing results from experiments with multiple inhibitors we can draw inferences about the major cell types and transporters involved. In cerebellum, glutamine and alanine transfer is dominated by system A, blockade of which has maximum effect on metabolism, with contributions from System N. Inhibition of neural system A isoform SNAT1 by MeAIB resulted in greatly decreased metabolite pools and reduced net fluxes but showed little effect on fluxes from [1,2-13C]acetate unlike inhibition of SNAT3 and other glutamine transporters by histidine where net fluxes from [1,2-13C]acetate are reduced by ~50%. We interpret the data as further evidence of not one but several glutamate/glutamine exchange pools. The impact of amino acid transport inhibition demonstrates that the cerebellum has tightly coupled cells and that glutamate/glutamine, as well as alanine cycling, play a major role in that part of the brain.

Keywords:  alanine; amino acid transporters; glutamine

DOI:  https://doi.org/10.3390/biom12091189
Int J Mol Sci. 2022 Sep 08. pii: 10387. [Epub ahead of print]23(18):

Serum Phospholipid Profile Changes in Gaucher Disease and Parkinson's Disease.

Laura López de Frutos, Francisco Almeida, Jessica Murillo-Saich, Vasco A Conceição, Monica Guma, Oswald Queheberger, Pilar Giraldo, Gabriel Miltenberger-Miltenyi.

  Alterations in the levels of serum sphingolipids and phospholipids have been reported in Gaucher disease and in Parkinson's disease, suggesting a potential role of these lipids as biomarkers. This project's objective is to detect novel associations and novel candidate biomarkers in the largest Spanish Gaucher and Parkinson diseases of the Iberian Peninsula. For that, 278 participants were included: 100 sporadic Parkinson's patients, 70 Gaucher patients, 15 GBA1-mutation-carrier Parkinson's patients and 93 controls. A serum lipidomics array including 10 phospholipid groups, 368 species, was performed using high-performance liquid chromatography-mass spectrometry. Lipid levels were compared between groups via multiple-regression analyses controlling for clinical and demographic parameters. Additionally, lipid levels were compared within the Gaucher and Parkinson's groups controlling for medication and/or disease severity. Results were controlled for robustness by filtering of non-detectable lipid values. There was an increase in the levels of phosphatidylcholine, with a simultaneous decrease in lyso-phosphatidylcholine, in the Gaucher, Parkinson's and GBA1-mutation-carrier Parkinson's patients vs. controls. Phosphatidylethanolamine, lyso- and plasmalogen-phosphatidylethanolamine were also increased in Gaucher and Parkinson's. Gaucher patients also showed an increase in lyso-phosphatidylserine and phosphatidylglycerol. While in the Gaucher and Parkinson's groups, velaglucerase alpha and dopamine agonists, respectively, showed positive associations with the lipid changes, miglustat treatment in Gaucher patients normalized the altered phosphatidylcholine/lyso-phosphatidylcholine ratio. In conclusion, Gaucher and Parkinson's patients showed changes in various serum phospholipid levels when compared with healthy controls, further supporting the role of such lipids in disease development and, possibly, as putative biomarkers. This hypothesis was reinforced by the normalizing effect of miglustat, and by controlling for data robustness, even though the limited number of participants, especially in the sub-distribution by treatment groups in GD requires validation in a larger number of patients.

Keywords:  GBA1; Gaucher disease; Parkinson’s disease; dopamine agonist; miglustat; plasma phospholipids

DOI:  https://doi.org/10.3390/ijms231810387
Brain Sci. 2022 Sep 04. pii: 1193. [Epub ahead of print]12(9):

Olive- and Coconut-Oil-Enriched Diets Decreased Secondary Bile Acids and Regulated Metabolic and Transcriptomic Markers of Brain Injury in the Frontal Cortexes of NAFLD Pigs.

Magdalena A Maj, Tanvi R Gehani, Chad Immoos, Mikaelah S Medrano, Rob K Fanter, Christine R Strand, Hunter Glanz, Brian D Piccolo, Mohammed K Abo-Ismail, Michael R La Frano, Rodrigo Manjarín.

  The objective of this study was to investigate the effect of dietary fatty acid (FA) saturation and carbon chain length on brain bile acid (BA) metabolism and neuronal number in a pig model of pediatric NAFLD. Thirty 20-day-old Iberian pigs, pair-housed in pens, were randomly assigned to receive one of three hypercaloric diets for 10 weeks: (1) lard-enriched (LAR; n = 5 pens), (2) olive-oil-enriched (OLI, n = 5), and (3) coconut-oil-enriched (COC; n = 5). Pig behavior and activity were analyzed throughout the study. All animals were euthanized on week 10 and frontal cortex (FC) samples were collected for immunohistochemistry, metabolomic, and transcriptomic analyses. Data were analyzed by multivariate and univariate statistics. No differences were observed in relative brain weight, neuronal number, or cognitive functioning between diets. Pig activity and FC levels of neuroprotective secondary BAs and betaine decreased in the COC and OLI groups compared with LAR, and paralleled the severity of NAFLD. In addition, OLI-fed pigs showed downregulation of genes involved in neurotransmission, synaptic transmission, and nervous tissue development. Similarly, COC-fed pigs showed upregulation of neurogenesis and myelin repair genes, which caused the accumulation of medium-chain acylcarnitines in brain tissue. In conclusion, our results indicate that secondary BA levels in the FCs of NAFLD pigs are affected by dietary FA composition and are associated with metabolic and transcriptomic markers of brain injury. Dietary interventions that aim to replace saturated FAs by medium-chain or monounsaturated FAs in high-fat hypercaloric diets may have a negative effect on brain health in NAFLD patients.

Keywords:  Iberian pigs; brain; metabolomics; neurodegeneration; pediatric model; transcriptomics

DOI:  https://doi.org/10.3390/brainsci12091193
Mol Ther. 2022 Sep 16. pii: S1525-0016(22)00558-5. [Epub ahead of print]

Treatment with THI, an inhibitor of Sphingosine-1-phosphate Lyase (SGPL1), modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease.

Giuseppe Pepe, Luca Capocci, Federico Marracino, Natalia Realini, Paola Lenzi, Katiuscia Martinello, Tiziana Francesca Bovier, Terry Jo Bichell, Pamela Scarselli, Clotilde Di Cicco, Aaron B Bowman, Filomena A Digilio, Sergio Fucile, Francesco Fornai, Andrea Armirotti, Rosanna Parlato, Alba Di Pardo, Vittorio Maglione.

  Huntington's disease (HD) is a fatal neurodegenerative disorder with no effective cure currently available. Over the past few years our research has shown that alterations in sphingolipid metabolism represent a critical determinant in HD pathogenesis. In particular, aberrant metabolism of sphingosine-1-phosphate (S1P) has been reported in multiple disease settings including human post-mortem brains from HD patients. In this study, we investigated the potential therapeutic effect of the inhibition of S1P degradative enzyme SGPL1, by the chronic administration of the THI inhibitor. We showed that THI mitigated motor dysfunctions in both mouse and fly models of HD. The compound evoked the activation of pro-survival pathways, normalized levels of BDNF, preserved white matter integrity and stimulated synaptic functions in HD mice. Metabolically, THI restored normal levels of hexosylceramides and stimulated the autophagic and lysosomal machinery, facilitating the reduction of nuclear inclusions of both wild type and mutant huntingtin proteins.

Keywords:  Glucosylceramide; Htt; Neurodegeneration; Neuroprotection; THI; Therapeutics

DOI:  https://doi.org/10.1016/j.ymthe.2022.09.004
J Pers Med. 2022 Aug 30. pii: 1418. [Epub ahead of print]12(9):

The Role of Sphingomyelin and Ceramide in Motor Neuron Diseases.

Gavin McCluskey, Colette Donaghy, Karen E Morrison, John McConville, William Duddy, Stephanie Duguez.

  Amyotrophic Lateral Sclerosis (ALS), Spinal Bulbar Muscular Atrophy (SBMA), and Spinal Muscular Atrophy (SMA) are motor neuron diseases (MNDs) characterised by progressive motor neuron degeneration, weakness and muscular atrophy. Lipid dysregulation is well recognised in each of these conditions and occurs prior to neurodegeneration. Several lipid markers have been shown to predict prognosis in ALS. Sphingolipids are complex lipids enriched in the central nervous system and are integral to key cellular functions including membrane stability and signalling pathways, as well as being mediators of neuroinflammation and neurodegeneration. This review highlights the metabolism of sphingomyelin (SM), the most abundant sphingolipid, and of its metabolite ceramide, and its role in the pathophysiology of neurodegeneration, focusing on MNDs. We also review published lipidomic studies in MNDs. In the 13 studies of patients with ALS, 12 demonstrated upregulation of multiple SM species and 6 demonstrated upregulation of ceramides. SM species also correlated with markers of clinical progression in five of six studies. These data highlight the potential use of SM and ceramide as biomarkers in ALS. Finally, we review potential therapeutic strategies for targeting sphingolipid metabolism in neurodegeneration.

Keywords:  Amyotrophic Lateral Sclerosis; ceramide; motor neuron disease; sphingolipid; sphingomyelin

DOI:  https://doi.org/10.3390/jpm12091418
Methods Mol Biol. 2022 ;2546 27-34

Tandem Mass Spectrometry for the Analysis of Plasma/Serum Acylcarnitines for the Diagnosis of Certain Organic Acidurias and Fatty Acid Oxidation Disorders.

David Scott, C Clinton Frazee, Bryce Heese, Uttam Garg.

  Acylcarnitines are formed in the mitochondria by esterification between carnitine and acyl-CoAs. This occurs enzymatically via carnitine acyltransferases. Specific acylcarnitines accumulate as a result of various organic acidurias and fatty acid oxidation disorders, and, thus, acylcarnitines profiles are used for the diagnosis of these disorders. Acylcarnitines monitoring can also be used for the follow-up of patients with these disorders. Tandem mass spectrometry (MS/MS) is the most commonly used method for the analysis of acylcarnitines. An MS/MS method for the quantification of a number of acylcarnitines is described. The method involves butylation of acylcarnitines using acidified butanol. Butylated acylcarnitines are analyzed using flow injection and precursor ion scan. Multiple-reaction monitoring (MRM) is used for the analysis of low-molecular-weight acylcarnitines.

Keywords:  Fatty acid oxidation defects; Inborn error of metabolism; Inherited metabolic disorders; Medium-chain acyl-CoA dehydrogenase deficiency; Organic acidemia; Organic acidurias; Tandem mass spectrometry

DOI:  https://doi.org/10.1007/978-1-0716-2565-1_3
Biomolecules. 2022 Sep 09. pii: 1270. [Epub ahead of print]12(9):

Phosphatidylethanolamine N-Methyltransferase Knockout Modulates Metabolic Changes in Aging Mice.

Qishun Zhou, Fangrong Zhang, Jakob Kerbl-Knapp, Melanie Korbelius, Katharina Barbara Kuentzel, Nemanja Vujić, Alena Akhmetshina, Gerd Hörl, Margret Paar, Ernst Steyrer, Dagmar Kratky, Tobias Madl.

  Phospholipid metabolism, including phosphatidylcholine (PC) biosynthesis, is crucial for various biological functions and is associated with longevity. Phosphatidylethanolamine N-methyltransferase (PEMT) is a protein that catalyzes the biosynthesis of PC, the levels of which change in various organs such as the brain and kidneys during aging. However, the role of PEMT for systemic PC supply is not fully understood. To address how PEMT affects aging-associated energy metabolism in tissues responsible for nutrient absorption, lipid storage, and energy consumption, we employed NMR-based metabolomics to study the liver, plasma, intestine (duodenum, jejunum, and ileum), brown/white adipose tissues (BAT and WAT), and skeletal muscle of young (9-10 weeks) and old (91-132 weeks) wild-type (WT) and PEMT knockout (KO) mice. We found that the effect of PEMT-knockout was tissue-specific and age-dependent. A deficiency of PEMT affected the metabolome of all tissues examined, among which the metabolome of BAT from both young and aged KO mice was dramatically changed in comparison to the WT mice, whereas the metabolome of the jejunum was only slightly affected. As for aging, the absence of PEMT increased the divergence of the metabolome during the aging of the liver, WAT, duodenum, and ileum and decreased the impact on skeletal muscle. Overall, our results suggest that PEMT plays a previously underexplored, critical role in both aging and energy metabolism.

Keywords:  NMR; PEMT; aging; intestine; knockout; liver; metabolomics; mice; white/brown adipose tissue

DOI:  https://doi.org/10.3390/biom12091270
Metabolites. 2022 Aug 31. pii: 822. [Epub ahead of print]12(9):

Associations of the Lipidome with Ageing, Cognitive Decline and Exercise Behaviours.

Maria Kadyrov, Luke Whiley, Belinda Brown, Kirk I Erickson, Elaine Holmes.

  One of the most recognisable features of ageing is a decline in brain health and cognitive dysfunction, which is associated with perturbations to regular lipid homeostasis. Although ageing is the largest risk factor for several neurodegenerative diseases such as dementia, a loss in cognitive function is commonly observed in adults over the age of 65. Despite the prevalence of normal age-related cognitive decline, there is a lack of effective methods to improve the health of the ageing brain. In light of this, exercise has shown promise for positively influencing neurocognitive health and associated lipid profiles. This review summarises age-related changes in several lipid classes that are found in the brain, including fatty acyls, glycerolipids, phospholipids, sphingolipids and sterols, and explores the consequences of age-associated pathological cognitive decline on these lipid classes. Evidence of the positive effects of exercise on the affected lipid profiles are also discussed to highlight the potential for exercise to be used therapeutically to mitigate age-related changes to lipid metabolism and prevent cognitive decline in later life.

Keywords:  ageing; cognition; exercise; lipidomics; liquid chromatography–mass spectrometry (LC–MS); metabolic phenotyping; metabolism; nuclear magnetic resonance spectroscopy (NMR)

DOI:  https://doi.org/10.3390/metabo12090822
Cereb Cortex. 2022 Sep 20. pii: bhac327. [Epub ahead of print]

N-acetylcysteine treatment mitigates loss of cortical parvalbumin-positive interneuron and perineuronal net integrity resulting from persistent oxidative stress in a rat TBI model.

Mustafa Q Hameed, Nathaniel Hodgson, Henry H C Lee, Andres Pascual-Leone, Paul C MacMullin, Ali Jannati, Sameer C Dhamne, Takao K Hensch, Alexander Rotenberg.

  Traumatic brain injury (TBI) increases cerebral reactive oxygen species production, which leads to continuing secondary neuronal injury after the initial insult. Cortical parvalbumin-positive interneurons (PVIs; neurons responsible for maintaining cortical inhibitory tone) are particularly vulnerable to oxidative stress and are thus disproportionately affected by TBI. Systemic N-acetylcysteine (NAC) treatment may restore cerebral glutathione equilibrium, thus preventing post-traumatic cortical PVI loss. We therefore tested whether weeks-long post-traumatic NAC treatment mitigates cortical oxidative stress, and whether such treatment preserves PVI counts and related markers of PVI integrity and prevents pathologic electroencephalographic (EEG) changes, 3 and 6 weeks after fluid percussion injury in rats. We find that moderate TBI results in persistent oxidative stress for at least 6 weeks after injury and leads to the loss of PVIs and the perineuronal net (PNN) that surrounds them as well as of per-cell parvalbumin expression. Prolonged post-TBI NAC treatment normalizes the cortical redox state, mitigates PVI and PNN loss, and - in surviving PVIs - increases per-cell parvalbumin expression. NAC treatment also preserves normal spectral EEG measures after TBI. We cautiously conclude that weeks-long NAC treatment after TBI may be a practical and well-tolerated treatment strategy to preserve cortical inhibitory tone post-TBI.

Keywords:  N-acetylcysteine; oxidative stress; parvalbumin-positive interneuron; perineuronal net; traumatic brain injury

DOI:  https://doi.org/10.1093/cercor/bhac327
Int J Mol Sci. 2022 Sep 16. pii: 10815. [Epub ahead of print]23(18):

Alteration of Fatty Acid Profile in Fragile X Syndrome.

Armita Abolghasemi, Maria Paulina Carullo, Ester Cisneros Aguilera, Asma Laroui, Rosalie Plantefeve, Daniela Rojas, Serine Benachenhou, María Victoria Ramírez, Mélodie Proteau-Lemieux, Jean-François Lepage, François Corbin, Mélanie Plourde, Mauricio Farez, Patricia Cogram, Artuela Çaku.

  Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder.

Keywords:  Fragile X; fatty acids; lipids; neurodevelopmental disorder; phospholipids

DOI:  https://doi.org/10.3390/ijms231810815
Medicina (Kaunas). 2022 Sep 16. pii: 1295. [Epub ahead of print]58(9):

Incidence and Risk Factors for Glucose Disturbances in Premature Infants.

Ivona Butorac Ahel, Kristina Lah Tomulić, Inge Vlašić Cicvarić, Marta Žuvić, Kristina Baraba Dekanić, Silvije Šegulja, Iva Bilić Čače.

   BACKGROUND AND OBJECTIVES: There are limited data regarding the incidence and risk factors for hypoglycemia, hyperglycemia, and unstable glycemia in preterm infants. The aim of the present study was to determine the incidence and risk factors associated with neonatal hypoglycemia, hyperglycemia, and unstable glycemia in preterm infants during the first seven days of life.
MATERIALS AND METHODS: This prospective study included preterm infants <37 weeks of gestation, admitted to the Neonatal Intensive Care Unit between January 2018 and December 2020. Based on blood glucose levels in the first week of life, infants were divided into the following four groups: normoglycemic, hypoglycemic, hyperglycemic, and unstable. Blood glucose levels were measured from capillary blood at the 1st, 3rd, 6th, and 12th hour of life during the first 24 h, and at least once a day from days 2 to 7, prefeed.
RESULTS: Of 445 enrolled infants, 20.7% (92/445) were categorized as hypoglycemic, 9.9% (44/445) as hyperglycemic, and 2.9% (13/445) as unstable, respectively. Hypoglycemia was most commonly observed among infants ≥34 weeks (27.9%), and hyperglycemia was most common among preterm infants <28 weeks (50%). Female gender increased the chances of developing hypoglycemia by three times. The decrease in gestational age by one week increased the chance of developing hyperglycemia by 1.9 times. Sepsis increased the chance of developing hyperglycemia seven times, respiratory distress syndrome five times, and mechanical ventilation three times, respectively.
CONCLUSIONS: Glucose disturbances in the early neonatal period in preterm infants are common and mostly asymptomatic. Therefore, careful blood glucose level monitoring is required in those infants, especially in late preterm infants, in order to prevent possible neurological complications.

Keywords:  glucose variability; hyperglycemia; hypoglycemia; preterm infant

DOI:  https://doi.org/10.3390/medicina58091295