bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022‒12‒18
forty-one papers selected by
Regina F. Fernández
Johns Hopkins University
  1. Astrocytes as metabolic suppliers to support neuronal activity and brain functions.
  2. How Alpha Linolenic Acid May Sustain Blood-Brain Barrier Integrity and Boost Brain Resilience against Alzheimer's Disease.
  3. Chronic Ketosis Modulates HIF1α-Mediated Inflammatory Response in Rat Brain.
  4. The Role of Ketogenic Diet in the Treatment of Neurological Diseases.
  5. Cilia bent out of shape over dysfunctional astrocyte mitochondria.
  6. Auts2 regulated autism-like behavior, glucose metabolism and oxidative stress in mice.
  7. Erythrocyte Membrane Docosahexaenoic Acid (DHA) and Lipid Profile in Preterm Infants at Birth and Over the First Month of Life: A Comparative Study with Infants at Term.
  8. Regional differences in the reduction in cerebral FDG uptake induced by the ketogenic diet.
  9. Singular versus combinatory glucose-sensitive signal control of metabolic sensor protein profiles in hypothalamic astrocyte cultures from each sex.
  10. Implications of p53 in mitochondrial dysfunction and Parkinson's disease.
  11. Exercise and mitochondrial remodeling to prevent age-related neurodegeneration.
  12. Genetic defects in peroxisome morphogenesis (Pex11β, DLP1, and NME3) affect DHA-phospholipid metabolism.
  13. The Metabolic Role of Ketogenic Diets in Treating Epilepsy.
  14. Altered expression of glycobiology-related genes in Parkinson's disease brain.
  15. Leucine 434 is essential for docosahexaenoic acid-induced augmentation of L-glutamate transporter current.
  16. Perioperative management of surgical orthodontic treatment in a patient with glucose transporter 1 deficiency: report of a case and review of the literature.
  17. Brain Glucose Metabolism and Aging: A 5-Year Longitudinal Study in a Large Positron Emission Tomography Cohort.
  18. The Effects of Dietary Interventions on Brain Aging and Neurological Diseases.
  19. Altered neurometabolite levels in the brains of patients with depression: A systematic analysis of magnetic resonance spectroscopy studies.
  20. Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments.
  21. Neuropathological Findings in Short-Chain enoyl-CoA Hydratase 1 Deficiency (ECHS1D): Case Report and Differential Diagnosis.
  22. Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.
  23. Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway-implications for Parkinson's disease.
  24. Ethyl EPA and ethyl DHA cause similar and differential changes in plasma lipid concentrations and lipid metabolism in subjects with low-grade chronic inflammation.
  25. Brain total creatine differs between primary progressive aphasia (PPA) subtypes and correlates with disease severity.
  26. Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy.
  27. Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines.
  28. Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
  29. Associations between Fatty Acid Intake and Tension-Type Headache: A Cross-Sectional Study.
  30. Astrocyte innate immune activation and injury amplification following experimental focal cerebral ischemia.
  31. Free-L-Cysteine improves corticosterone-induced behavioral deficits, oxidative stress and neurotransmission in rats.
  32. Spatial and temporal alterations of developing oligodendrocytes induced by repeated sevoflurane exposure in neonatal mice.
  33. Paternal transmission of behavioural and metabolic traits induced by postnatal stress to the 5th generation in mice.
  34. Integrated transcriptomic and metabolomic profiling reveals dysregulation of purine metabolism during the acute phase of spinal cord injury in rats.
  35. Postnatal Exposure to Brief Hypoxia Alters Brain VEGF Expression and Capillary Density in Adult Mice.
  36. Sterol dysregulation in Smith-Lemli-Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk.
  37. Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury.
  38. Ketogenic Diets in the Management of Lennox-Gastaut Syndrome-Review of Literature.
  39. Generation of an induced pluripotent stem cell line (SHCDNi007-A) from a patient with pyruvate carboxylase deficiency carrying compound heterozygous (c.182 T > C/ c.2581G > A) variants in PC.
  40. Lipidomics Changes in a Murine Model of Neuropsychiatric Lupus.
  41. Short-term high-fat diet alters the mouse brain magnetic resonance imaging parameters consistently with neuroinflammation on males and metabolic rearrangements on females. A pre-clinical study with an optimized selection of linear mixed-effects models.
  1. Essays Biochem. 2022 Dec 12. pii: EBC20220080. [Epub ahead of print]
    Astrocytes as metabolic suppliers to support neuronal activity and brain functions.
    Hélène Roumes, Luc Pellerin, Anne-Karine Bouzier-Sore.
      Energy metabolism is essential for brain function. In recent years, lactate shuttling between astrocytes and neurons has become a fundamental concept of neuroenergetics. However, it remains unclear to what extent this process is critical for different aspects of cognition, their underlying mechanisms, as well as for the signals used to monitor brain activation.
    Keywords:  Astrocyte; Brain metabolism; Lactate
    DOI:  https://doi.org/10.1042/EBC20220080
  2. Nutrients. 2022 Nov 30. pii: 5091. [Epub ahead of print]14(23):
    How Alpha Linolenic Acid May Sustain Blood-Brain Barrier Integrity and Boost Brain Resilience against Alzheimer's Disease.
    Alicia Leikin-Frenkel, Michal Schnaider Beeri, Itzik Cooper.
      Cognitive decline, the primary clinical phenotype of Alzheimer's disease (AD), is currently attributed mainly to amyloid and tau protein deposits. However, a growing body of evidence is converging on brain lipids, and blood-brain barrier (BBB) dysfunction, as crucial players involved in AD development. The critical role of lipids metabolism in the brain and its vascular barrier, and its constant modifications particularly throughout AD development, warrants investigation of brain lipid metabolism as a high value therapeutic target. Yet, there is limited knowledge on the biochemical and structural roles of lipids in BBB functionality in AD. Within this framework, we hypothesize that the ApoE4 genotype, strongly linked to AD risk and progression, may be related to altered fatty acids composition in the BBB. Interestingly, alpha linolenic acid (ALA), the precursor of the majoritarian brain component docosahexaenoic acid (DHA), emerges as a potential novel brain savior, acting via BBB functional improvements, and this may be primarily relevant to ApoE4 carriers.
    Keywords:  Alzheimer’s dementia; Alzheimer’s disease; alpha linolenic acid; blood–brain barrier; cardiocerebrovascular diseases; fatty acids; vascular cognitive impairment
    DOI:  https://doi.org/10.3390/nu14235091
  3. Adv Exp Med Biol. 2022 ;1395 75-79
    Chronic Ketosis Modulates HIF1α-Mediated Inflammatory Response in Rat Brain.
    Aarti Sethuraman, Prahlad Rao, Atul Pranay, Kui Xu, Joseph LaManna, Michelle A Puchowicz.
      Hypoxia inducible factor alpha (HIF1α) is associated with neuroprotection conferred by diet-induced ketosis but the underlying mechanism remains unclear. In this study we use a ketogenic diet in rodents to induce a metabolic state of chronic ketosis, as measured by elevated blood ketone bodies. Chronic ketosis correlates with neuroprotection in both aged and following focal cerebral ischaemia and reperfusion (via middle cerebral artery occlusion, MCAO) in mouse and rat models. Ketone bodies are known to be used efficiently by the brain and metabolism of ketone bodies is associated with increased cytosolic succinate levels that inhibits prolyl hydroxylases allowing HIF1α to accumulate. Ketosis also regulates inflammatory pathways, and HIF1α is reported to be essential for gene expression of interleukin10 (IL10). Therefore we hypothesised that ketosis-stabilised HIF1α modulates the expression of inflammatory cytokines orchestrating neuroprotection. To test changes in cytokine levels in rodent brain, eight-week-old rats were fed either the standard chow diet (SD) or the ketogenic (KG) diet for 4 weeks before ischaemia experiments (MCAO) were performed and the brain tissues were collected. Consistent with our hypothesis, immunoblotting analysis shows IL10 levels were significantly higher in KG diet rat brain compared to SD, whereas the TNFα and IL6 levels were significantly lower in the brains of KG diet fed group.
    Keywords:  Acetoacetate; Beta-hydroxybutyrate; IL10; Ketogenic diet; Neuroprotection; Succinate
    DOI:  https://doi.org/10.1007/978-3-031-14190-4_13
  4. Nutrients. 2022 Nov 24. pii: 5003. [Epub ahead of print]14(23):
    The Role of Ketogenic Diet in the Treatment of Neurological Diseases.
    Damian Dyńka, Katarzyna Kowalcze, Agnieszka Paziewska.
      Over a hundred years of study on the favourable effect of ketogenic diets in the treatment of epilepsy have contributed to a long-lasting discussion on its potential influence on other neurological diseases. A significant increase in the number of scientific studies in that field has been currently observed. The aim of this paper is a widespread, thorough analysis of the available scientific evidence in respect of the role of the ketogenic diet in the therapy of neurological diseases such as: epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and migraine. A wide range of the mechanisms of action of the ketogenic diet has been demonstrated in neurological diseases, including, among other effects, its influence on the reduction in inflammatory conditions and the amount of reactive oxygen species (ROS), the restoration of the myelin sheath of the neurons, the formation and regeneration of mitochondria, neuronal metabolism, the provision of an alternative source of energy for neurons (ketone bodies), the reduction in glucose and insulin concentrations, the reduction in amyloid plaques, the induction of autophagy, the alleviation of microglia activation, the reduction in excessive neuronal activation, the modulation of intestinal microbiota, the expression of genes, dopamine production and the increase in glutamine conversion into GABA. The studies discussed (including randomised controlled studies), conducted in neurological patients, have stressed the effectiveness of the ketogenic diet in the treatment of epilepsy and have demonstrated its promising therapeutic potential in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and migraine. A frequent advantage of the diet was demonstrated over non-ketogenic diets (in the control groups) in the therapy of neurological diseases, with simultaneous safety and feasibility when conducting the nutritional model.
    Keywords:  Alzheimer’s disease (AD); Parkinson’s disease (PD); anti-inflammatory; brain; epilepsy; high fat; inflammatory; ketogenic; ketogenic diet; ketone bodies; low carb; migraine; multiple sclerosis (MS); neuroinflammation; neurological diseases; neurone; neuroplasticity; neurotransmitters; nutrition; prevention; treatment
    DOI:  https://doi.org/10.3390/nu14235003
  5. J Cell Biol. 2023 Jan 02. pii: e202211123. [Epub ahead of print]222(1):
    Cilia bent out of shape over dysfunctional astrocyte mitochondria.
    Rachel M Bear, Tamara Caspary.
      Mitochondrial dysfunction in astrocytes drives neurodegenerative brain pathology. In this issue, Ignatenko et al. (2022. J. Cell. Biol.https://doi.org/10.1083/jcb.202203019) discover a novel connection between cilia and mitochondria in astrocytes, whereby mitochondrial dysfunction leads to abnormal cilia structure and a motile cilia program.
    DOI:  https://doi.org/10.1083/jcb.202211123
  6. Exp Neurol. 2022 Dec 13. pii: S0014-4886(22)00323-5. [Epub ahead of print] 114298
    Auts2 regulated autism-like behavior, glucose metabolism and oxidative stress in mice.
    Min Liu, Yimeng Chen, Miao Sun, Yingjie Du, Yafan Bai, Guiyu Lei, Congya Zhang, Mingru Zhang, Yue Zhang, Chunhua Xi, Yulong Ma, Guyan Wang.
      Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormal social behavior and communication. The autism susceptibility candidate 2 (AUTS2) gene has been associated with multiple neurological diseases, including ASD. Glucose metabolism plays an important role in social behaviors associated with ASD, but the potential role of AUTS2 in glucose metabolism has not been studied. Here, we generated Auts2flox/flox; Emx1Cre+ conditional knockout mice with Auts2 deletion specifically in Exm1-positive neurons in the brain (Auts2-CKO mice) to evaluate the effects of Auts2 knockdown on social behaviors and metabolic pathways. Auts2-CKO mice exhibited ASD-like behaviors, including impaired social interactions and repetitive grooming behaviors. At the molecular level, we found that Auts2 knockdown reduced brain glucose uptake and inhibited the pentose phosphate pathway. Auts2 knockdown also resulted in signs of oxidative stress, and we documented increased levels of reactive oxygen species and malondialdehyde as well as decreased levels of antioxidant molecules, including glutathione and superoxide dismutases in Auts2-cKO mouse brains compared to controls. Finally, Auts2 knockdown significantly disrupted mitochondrial homeostasis and inhibited activity of the SIRT1-SIRT3 axis. Taken together, our findings indicate that loss of AUTS2 expression in Emx1-expressing cells induces multiple changes in metabolic pathways that have been linked to the pathology of ASD. Further characterization of the role of AUTS2 in Emx1-expressing cells in regulating the metabolism of brain neurons may identify opportunities to treat ASD and AUTS2-deficiency disorders with metabolism-targeted therapies.
    Keywords:  AUTS2; Autism spectrum disorder; Glucose metabolism; Mitochondria; Oxidative stress; Pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.expneurol.2022.114298
  7. Nutrients. 2022 Nov 22. pii: 4956. [Epub ahead of print]14(23):
    Erythrocyte Membrane Docosahexaenoic Acid (DHA) and Lipid Profile in Preterm Infants at Birth and Over the First Month of Life: A Comparative Study with Infants at Term.
    Félix Castillo Salinas, Alicia Montaner Ramón, Félix-Joel Castillo Ferrer, Adrià Domingo-Carnice, Begoña Cordobilla, Joan Carles Domingo.
      An observational comparative study was designed to assess the fatty acids profile in erythrocyte membrane phospholipids of 30 preterm neonates (<32 weeks gestation) at birth and after 1 month of life versus a convenience sample of 10 infants born at term. The panel of fatty acids included the families and components of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and n-6 and n-3 polyunsaturated fatty acids (PUFAs) as well as enzyme activity indexes and fatty acids ratios. At birth, the comparison of fatty acid families between preterm and term neonates showed a significantly higher content of SFAs and n-6 PUFAs, and a significantly lower content of MUFAs and n-3 PUFAs in the preterm group. After 30 days of life, significantly higher levels of n-6 PUFAs and significantly lower levels of n-3 PUFAs among preterm neonates persisted. At 30 days of birth, n-6 PUFA/n-3 PUFA and arachidonic acid (ARA) ARA/DHA remained significantly elevated, and DHA sufficiency index significantly decreased in the preterm group. The pattern of n-3 PUFA deficiency at birth and sustained for the first month of life would support the need of milk banking fortified with DHA and the use of DHA supplementation in breastfeeding mothers.
    Keywords:  arachidonic acid; docosahexaenoic acid; eicosapentaenoic acid; erythrocyte membrane; linoleic acid; lipid profile; preterm infants
    DOI:  https://doi.org/10.3390/nu14234956
  8. Eur J Hybrid Imaging. 2022 Dec 15. 6(1): 29
    Regional differences in the reduction in cerebral FDG uptake induced by the ketogenic diet.
    O A Bennett, S C Ramsay, E Malacova, P Bourgeat, S J Goodman, C J Dunn, B M Robinson, K Lee, D A Pattison.
      BACKGROUND: The postulated benefits of the ketogenic diet in the management of multiple medical conditions have seen more patients who are in therapeutic ketosis attending 18F-FDG PET scans. This study aimed to investigate the effect of ketosis on cerebral glucose metabolism in a clinical PET scanning environment using 18F-FDG uptake as a surrogate marker.METHODS: A retrospective audit was conducted of the brain 18F-FDG uptake in 52 patients who underwent PET scans for possible cardiac sarcoidosis or suspected intracardiac infection, following a ketogenic diet and prolonged fasting. SUVbw for whole brain and separate brain regions was compared with serum glucose and serum ketone body (beta-hydroxybutyrate) levels.
    RESULTS: The expected negative association between serum glucose levels and whole brain 18F-FDG uptake was confirmed. A reduction in SUVbw due to increasing serum ketones levels was also observed that was independent of and in addition to the effects of glucose. The magnitude of the reduction in SUVbw related to serum glucose level and serum ketone level was found to be greater in the precuneus than in the cerebellum or whole brain.
    CONCLUSION: In a real-world clinical PET setting, cerebral 18F-FDG uptake appears to be affected by glycaemia and ketonaemia. This means when assessing the brain, both serum glucose and ketone levels need to be considered when SUVs are used to distinguish between pathologic and physiologic states. The magnitude of this effect appears to vary between different brain regions. This regional difference should be taken into consideration when selecting the appropriate brain region for SUV normalisation, particularly when undertaking database comparison in the assessment of dementia.
    Keywords:  Alzheimer’s disease; Cerebral glucose metabolism; Dementia; FDG PET; Ketosis
    DOI:  https://doi.org/10.1186/s41824-022-00150-5
  9. Transl Neurosci. 2022 Jan 01. 13(1): 408-420
    Singular versus combinatory glucose-sensitive signal control of metabolic sensor protein profiles in hypothalamic astrocyte cultures from each sex.
    Abdulrahman Alhamyani, Prabhat R Napit, Khaggeswar Bheemanapally, Paul W Sylvester, Karen P Briski.
      Brain metabolic-sensory targets for modulatory glucose-sensitive endocrine and neurochemical signals remain unidentified. A hypothalamic astrocyte primary culture model was here used to investigate whether glucocorticoid receptor (GR) and noradrenergic signals regulate astrocyte glucose (glucose transporter-2 [GLUT2], glucokinase) and/or energy (5'-AMP-activated protein kinase [AMPK]) sensor reactivity to glucoprivation by sex. Glucose-supplied astrocytes of each sex showed increased GLUT2 expression after incubation with the GR agonist dexamethasone (DEX) or norepinephrine (NE); DEX plus NE (DEX/NE) augmented GLUT2 in the female, but not in male. Glucoprivation did not alter GLUT2 expression, but eliminated NE regulation of this protein in both sexes. Male and female astrocyte glucokinase profiles were refractory to all drug treatments, but were down-regulated by glucoprivation. Glucoprivation altered AMPK expression in male only, and caused divergent sex-specific changes in activated, i.e., phosphoAMPK (pAMPK) levels. DEX or DEX/NE inhibited (male) or stimulated (female) AMPK and pAMPK proteins in both glucose-supplied and -deprived astrocytes. In male, NE coincidently up-regulated AMPK and inhibited pAMPK profiles in glucose-supplied astrocytes; these effects were abolished by glucoprivation. In female, AMPK profiles were unaffected by NE irrespective of glucose status, whereas pAMPK expression was up-regulated by NE only during glucoprivation. Present outcomes document, for each sex, effects of glucose status on hypothalamic astrocyte glucokinase, AMPK, and pAMPK protein expression and on noradrenergic control of these profiles. Data also show that DEX and NE regulation of GLUT2 is sex-monomorphic, but both stimuli impose divergent sex-specific effects on AMPK and pAMPK. Further effort is warranted to characterize mechanisms responsible for sex-dimorphic GR and noradrenergic governance of hypothalamic astrocyte energy sensory function.
    Keywords:  AMPK; GLUT2; dexamethasone; glucocorticoid receptor; glucokinase; norepinephrine
    DOI:  https://doi.org/10.1515/tnsci-2022-0259
  10. Int J Neurosci. 2022 Dec 14. 1-22
    Implications of p53 in mitochondrial dysfunction and Parkinson's disease.
    Yi-Fang Wang, Ying-Di Wang, Song Gao, Wei Sun.
      Mitochondria are vital subcellular organelles for that maintain cellular function, and mitochondrial defect and impairment are primary causes of dopaminergic neuron degeneration in Parkinson's disease (PD). P53 is a multifunctional protein implicated in the regulation of diverse cellular processes via transcription-dependent and transcription-independent mechanisms. Increasing evidence has revealed that mitochondrial dysfunction-associated dopaminergic neuron degeneration is tightly regulated by p53 in PD pathogenesis. Neurodegenerative stress triggers p53 activation, which induces mitochondrial changes, including transmembrane permeability, reactive oxygen species production, Ca2+ overload, electron transport chain defects and other dynamic alterations, and these changes contribute to neurodegeneration and are linked closely with PD occurrence and development. P53 inhibition has been shown to attenuate mitochondrial dysfunction and protect dopaminergic neurons from degeneration under conditions of neurodegenerative stress, and thus, p53 appears to be a potential target for neuroprotective therapy. We review the contributions of p53 to mitochondrial changes leading to apoptosis and the subsequent degeneration of dopaminergic neurons to advance the understanding of the underlying molecular mechanisms and provide a potential therapeutic target for PD treatment.
    Keywords:  P53; Parkinson’s disease; mitochondrial dysfunction; neurodegeneration
    DOI:  https://doi.org/10.1080/00207454.2022.2158824
  11. J Appl Physiol (1985). 2022 Dec 15.
    Exercise and mitochondrial remodeling to prevent age-related neurodegeneration.
    Colleen L O'Reilly, Benjamin F Miller, Tommy L Lewis.
      Healthy brain activity requires precise ion and energy management creating a strong reliance on mitochondrial function. Age-related neurodegeneration leads to a decline in mitochondrial function and increased oxidative stress, with associated declines in mitochondrial mass, respiration capacity, and respiration efficiency. The interdependent processes of mitochondrial protein turnover and mitochondrial dynamics, known together as mitochondrial remodeling, play essential roles in mitochondrial health and therefore brain function. This mini-review describes the role of mitochondria in neurodegeneration and brain health, current practices for assessing both aspects of mitochondrial remodeling, and how exercise mitigates the adverse effects of aging in the brain. Exercise training elicits functional adaptations to improve brain health, and current literature strongly suggests that mitochondrial remodeling plays a vital role in these positive adaptations. Despite substantial implications that the two aspects of mitochondrial remodeling are interdependent, very few investigations have simultaneously measured mitochondrial dynamics and protein synthesis. An improved understanding of the partnership between mitochondrial protein turnover and mitochondrial dynamics will provide a better understanding of their role in both brain health and disease, as well as how they induce protection following exercise.
    Keywords:  brain; exercise; mitochondria; mitochondria remodeling; neurodegeneration
    DOI:  https://doi.org/10.1152/japplphysiol.00611.2022
  12. J Inherit Metab Dis. 2022 Dec 15.
    Genetic defects in peroxisome morphogenesis (Pex11β, DLP1, and NME3) affect DHA-phospholipid metabolism.
    Yuichi Abe, Ronald J A Wanders, Hans R Waterham, Hanna Mandel, Tzipora C Falik-Zaccai, Naotada Ishihara, Yukio Fujiki.
      Peroxisomes are essential organelles involved in lipid metabolisms including plasmalogen biosynthesis and β-oxidation of very long-chain fatty acids. Peroxisomes proliferate by growth and division of pre-existing peroxisomes. The peroxisomal membrane is elongated by Pex11β and then divided by the dynamin-like GTPase, DLP1 (also known as DRP1 encoded by DNM1L gene), which also functions as a fission factor for mitochondria. Nucleoside diphosphate kinase 3 (NME3) localized in both peroxisomes and mitochondria generates GTP for DLP1 activity. Deficiencies of either of these factors induce abnormal morphology of peroxisomes and/or mitochondria, and are associated with central nervous system dysfunction. To investigate whether the impaired division of peroxisomes affects lipid metabolisms, we assessed the phospholipid composition of cells lacking each of the different division factors. In fibroblasts from the patients deficient in DLP1, NME3, or Pex11β, docosahexaenoic acid (DHA, C22:6)-containing phospholipids were found to be decreased. Conversely, the levels of several fatty acids such as arachidonic acid (AA, C20:4) and oleic acid (C18:1) were elevated. Mouse embryonic fibroblasts from Drp1- and Pex11β-knockout mice also showed a decrease in the levels of phospholipids containing DHA and AA. Collectively, these results suggest that the dynamics of organelle morphology exert marked effects on the fatty acid composition of phospholipids. This article is protected by copyright. All rights reserved.
    Keywords:  Pex11β; dynamin-like protein 1 (DLP1); impaired peroxisome division; lipidomics; nucleoside diphosphate kinase 3 (NME3); polyunsaturated fatty acid
    DOI:  https://doi.org/10.1002/jimd.12582
  13. Nutrients. 2022 Nov 29. pii: 5074. [Epub ahead of print]14(23):
    The Metabolic Role of Ketogenic Diets in Treating Epilepsy.
    Kaleem Imdad, Turki Abualait, Ammara Kanwal, Ziyad Tareq AlGhannam, Shahab Bashir, Anum Farrukh, Sahir Hameed Khattak, Raidah Albaradie, Shahid Bashir.
      Epilepsy is a long-term neurological condition that results in recurrent seizures. Approximately 30% of patients with epilepsy have drug-resistant epilepsy (DRE). The ketogenic diet (KD) is considered an effective alternative treatment for epileptic patients. The aim of this study was to identify the metabolic role of the KD in epilepsy. Ketone bodies induce chemical messengers and alterations in neuronal metabolic activities to regulate neuroprotective mechanisms towards oxidative damage to decrease seizure rate. Here, we discuss the role of KD on epilepsy and related metabolic disorders, focusing on its mechanism of action, favorable effects, and limitations. We describe the significant role of the KD in managing epilepsy disorders.
    Keywords:  biomarkers; drug-resistant epilepsy; epilepsy; ketogenic diet; parameters
    DOI:  https://doi.org/10.3390/nu14235074
  14. Front Mol Neurosci. 2022 ;15 1078854
    Altered expression of glycobiology-related genes in Parkinson's disease brain.
    Jay S Schneider, Garima Singh.
      The precise mechanisms initiating and perpetuating the cellular degeneration in Parkinson's disease (PD) remain unclear. There is decreased expression of the main brain gangliosides, and GM1 ganglioside in particular, in the PD brain along with decreased expression of the genes coding for the glycosyltranferase and the sialyltransferase responsible for the synthesis of these brain gangliosides. However, potentially important pathogenic mechanisms contributing to the neurodegeneration in PD may also include altered levels of expression of genes involved in glycosylation, sialylation and sphingolipid synthesis and metabolism. Although various studies have described pathological lipid and glycolipid changes in PD brain, there have been limited studies of expression of glycobiology-related genes in PD brain. The current study was performed as an initial attempt to gain new information regarding potential changes in glycoprotein and glycolipid-related genes in PD by investigating the gene expression status for select glycosyltransferases, sialyltransferases, sialidases, sphingosine kinases, and lysosomal enzymes in the substantia nigra and putamen from patients with PD and neurologically normal controls. Results showed altered expression of glycosyltransferase genes (B3GALT2 and B4GALT1) potentially involved in microglial activation and neuroinflammation, sphingosine-1-phosphate (S1P) modulators (SPHK1, SPHK2, and SGPL1) involved in sphingolipid synthesis and metabolism, polysialyltransferase genes (ST8SIA2 and ST8SIA4) that encode enzymes responsible for polysialic acid (polySia) biosynthesis, and the sialidase NEU4, expression of which has been linked to the clearance of storage materials from lysosomes. The data presented here underscore the complexity of the glycolipid/sphingolipid dysregulation in the PD brain and continued and expanded study of these processes may not only provide a greater understanding of the complex roles of aberrant glycosylation sialylation, and sphingolipid synthesis/metabolism in the pathophysiology of PD but may identify potential druggable targets for PD therapeutics.
    Keywords:  Parkinson’s disease; gene expression; glycolipid; putamen; sphingolipid; substantia nigra
    DOI:  https://doi.org/10.3389/fnmol.2022.1078854
  15. J Biol Chem. 2022 Dec 09. pii: S0021-9258(22)01236-4. [Epub ahead of print] 102793
    Leucine 434 is essential for docosahexaenoic acid-induced augmentation of L-glutamate transporter current.
    Kanako Takahashi, Luying Chen, Misa Sayama, Mian Wu, Mariko Kato Hayashi, Tomohiko Irie, Tomohiko Ohwada, Kaoru Sato.
      Astrocytic excitatory amino acid transporter 2 (EAAT2) plays a major role in removing the excitatory neurotransmitter L-glutamate (L-Glu) from synaptic clefts in the forebrain to prevent excitotoxicity. Polyunsaturated fatty acids such as docosahexaenoic acid (DHA, 22:6 n-3) enhance synaptic transmission, and their target molecules include EAATs. Here, we aimed to investigate the effect of DHA on EAAT2 and identify the key amino acid for DHA/EAAT2 interaction by electrophysiological recording of L-Glu-induced current in Xenopus oocytes transfected with EAATs, their chimeras, and single mutants. DHA transiently increased the amplitude of EAAT2, but tended to decrease that of EAAT1, another astrocytic EAAT. Single mutation of leucine (Leu) 434 to alanine (Ala) completely suppressed the augmentation by DHA, while mutation of EAAT1 Ala 435 (corresponding to EAAT2 Leu434) to Leu changed the effect from suppression to augmentation. Other polyunsaturated fatty acids (PUFAs) (docosapentaenoic acid, eicosapentaenoic acid, arachidonic acid, and a-linolenic acid) similarly augmented the EAAT2 current and suppressed the EAAT1 current. Finally, our docking analysis suggested the most stable docking site is the lipid crevice of EAAT2, in close proximity to the L-Glu and sodium binding sites, suggesting that the DHA/Leu434 interaction might affect the elevator-like slide and/or the shapes of the other binding sites. Collectively, our results highlight a key molecular detail in the DHA-induced regulation of synaptic transmission involving EAATs.
    Keywords:  astrocyte; electrophysiology; glutamate; polyunsaturated fatty acid (PUFA); transporter
    DOI:  https://doi.org/10.1016/j.jbc.2022.102793
  16. Perioper Med (Lond). 2022 Dec 16. 11(1): 55
    Perioperative management of surgical orthodontic treatment in a patient with glucose transporter 1 deficiency: report of a case and review of the literature.
    Nishiyama Kyoko, Hamada Masakazu, Nabatame Shin, Shimizu Hidetaka, Uzawa Narikazu.
      INTRODUCTION: Glucose transporter 1 (GLUT1) deficiency is a rare cerebral metabolic disorder caused by the shortage of glucose supply to the brain. For this disease, ketogenic diet therapy is essential. In addition, perioperative management requires not only the continuation of ketogenic diet therapy but also the management of nausea/vomiting, diarrhea, seizures, and infection. However, there have been few reports regarding oral and maxillofacial surgery.CASE PRESENTATION: We describe a patient with GLUT1 deficiency who underwent orthognathic surgery. An 18-year-old man was referred to our hospital with the chief complaint of mandibular regression. Surgical tolerance was assessed by a fasting test and tooth extraction under general anesthesia, and orthognathic surgery was then performed. For orthognathic surgery, the mandibular dentition had scissor-like occlusion, and it was difficult to arrange the mandible. Therefore, we decided to perform maxillary osteotomy first. After the mandibular dentition was arranged by maxillary osteotomy, sagittal split ramus osteotomy (SSRO) was performed. Intermaxillary fixation (IMF) was necessary for SSRO, and caution was needed to prevent suffocation. The orthognathic surgery was successful, although complications, such as vomiting, diarrhea, and seizures, developed.
    CONCLUSION: Surgical orthodontic treatment in GLUT1 deficiency can be performed relatively safely by maintaining the diet, taking measures against epilepsy and vomiting, and using antimicrobial agents in close collaboration with pediatricians, anesthesiologists, pharmacists, and nutritionists.
    Keywords:  Glucose transporter type 1 (GLUT1) deficiency; Jaw deformity; Ketogenic diet; Orthognathic surgery; Perioperative management
    DOI:  https://doi.org/10.1186/s13741-022-00287-8
  17. Diabetes Care. 2022 Dec 15. pii: dc221872. [Epub ahead of print]
    Brain Glucose Metabolism and Aging: A 5-Year Longitudinal Study in a Large Positron Emission Tomography Cohort.
    Kyoungjune Pak, Tuulia Malén, Severi Santavirta, Seunghyeon Shin, Hyun-Yeol Nam, Sven De Maeyer, Lauri Nummenmaa.
      
    DOI:  https://doi.org/10.2337/dc22-1872
  18. Nutrients. 2022 Nov 30. pii: 5086. [Epub ahead of print]14(23):
    The Effects of Dietary Interventions on Brain Aging and Neurological Diseases.
    Fleur Lobo, Jonathan Haase, Sebastian Brandhorst.
      Dietary interventions can ameliorate age-related neurological decline. Decades of research of in vitro studies, animal models, and clinical trials support their ability and efficacy to improve behavioral outcomes by inducing biochemical and physiological changes that lead to a more resilient brain. Dietary interventions including calorie restriction, alternate day fasting, time restricted feeding, and fasting mimicking diets not only improve normal brain aging but also slow down, or even reverse, the progression of neurological diseases. In this review, we focus on the effects of intermittent and periodic fasting on improving phenotypic outcomes, such as cognitive and motor-coordination decline, in the normal aging brain through an increase in neurogenesis and synaptic plasticity, and decrease in neuroinflammation, mitochondrial dysfunction, and oxidative stress. We summarize the results of various dietary interventions in animal models of age-related neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, and Multiple Sclerosis and discuss the results of clinical trials that explore the feasibility of dietary interventions in the prevention and treatment of these diseases.
    Keywords:  Alzheimer’s; Parkinson’s; aging; brain; epilepsy; intermittent fasting; multiple sclerosis; neurological diseases; periodic fasting
    DOI:  https://doi.org/10.3390/nu14235086
  19. J Affect Disord. 2022 Dec 12. pii: S0165-0327(22)01380-5. [Epub ahead of print]
    Altered neurometabolite levels in the brains of patients with depression: A systematic analysis of magnetic resonance spectroscopy studies.
    Xiongfei Xie, Yan Shi, Lin Ma, Wenqin Yang, Juncai Pu, Yiqing Shen, Yiyun Liu, Hanping Zhang, Fajin Lv, Liangbo Hu.
      BACKGROUND: Numerous magnetic resonance spectroscopy (MRS) studies have reported metabolic abnormalities in the brains of patients with depression, although inconsistent results have been reported. The aim of this study was to explore changes in neurometabolite levels in patients with depression across large-scale MRS studies.METHOD: A total of 307 differential metabolite entries associated with depression were retrieved from 180 MRS studies retrieved from the Metabolite Network of Depression Database. The vote-counting method was used to identify consistently altered metabolites in the whole brain and specific brain regions of patients with depression.
    RESULTS: Only few differential neurometabolites showed a stable change trend. The levels of total choline (tCho) and the tCho/N-acetyl aspartate (NAA) ratio were consistently higher in the brains of patients with depression, and that the levels of NAA, glutamate and glutamine (Glx), and gamma-aminobutyric acid (GABA) were lower. For specific brain regions, we found lower Glx levels in the prefrontal cortex and lower GABA concentrations in the occipital cortex. We also found lower concentrations of NAA in the anterior cingulate cortex and prefrontal cortex. The levels of tCho were higher in the prefrontal cortex and putamen.
    CONCLUSION: Our results revealed that most altered neurometabolites in previous studies lack of adequate reproducibility. Through vote-counting method with large-scale studies, downregulation of glutamatergic neurometabolites, impaired neuronal integrity, and disturbed membrane metabolism were found in the pathobiology of depression, which contribute to existing knowledge of neurometabolic changes in depression. Further studies based on a larger dataset are needed to confirm our findings.
    Keywords:  Brain; Depression; Magnetic resonance spectroscopy; Metabolite
    DOI:  https://doi.org/10.1016/j.jad.2022.12.020
  20. Int J Mol Sci. 2022 Dec 02. pii: 15197. [Epub ahead of print]23(23):
    Age-Related Decline in Nrf2/ARE Signaling Is Associated with the Mitochondrial DNA Damage and Cognitive Impairments.
    Artem P Gureev, Victoria G Khorolskaya, Irina S Sadovnikova, Ekaterina A Shaforostova, Vadim R Cherednichenko, Inna Y Burakova, Egor Y Plotnikov, Vasily N Popov.
      In this research, we compared the cognitive parameters of 2-, 7-, and 15-month-old mice, changes in mitochondrial DNA (mtDNA) integrity and expression of genes involved in the nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. We showed an age-related decrease in the Nfe2l2 expression in the cerebral cortex, not in the hippocampus. At the same time, we find an increase in the mtDNA copy number in the cerebral cortex, despite the lack of an increase in gene expression, which is involved in the mitochondrial biogenesis regulation. We suppose that increase in mtDNA content is associated with mitophagy downregulation. We supposed that mitophagy downregulation may be associated with an age-related increase in the mtDNA damage. In the hippocampus, we found a decrease in the Bdnf expression, which is involved in the pathways, which play an essential role in regulating long-term memory formation. We showed a deficit of working and reference memory in 15-month-old-mice in the water Morris maze, and a decrease in the exploratory behavior in the open field test. Cognitive impairments in 15-month-old mice correlated with a decrease in Bdnf expression in the hippocampus, Nfe2l2 expression, and an increase in the number of mtDNA damage in the cerebral cortex. Thus, these signaling pathways may be perspective targets for pharmacological intervention to maintain mitochondrial quality control, neuronal plasticity, and prevent the development of age-related cognitive impairment.
    Keywords:  Morris water maze; aging; brain-derived neurotrophic factor; cognitive deficit; mammalian target of rapamycin complex 1; mitochondrial DNA damage; nuclear erythroid 2-related factor 2
    DOI:  https://doi.org/10.3390/ijms232315197
  21. Pediatr Dev Pathol. 2022 Dec 14. 10935266221134650
    Neuropathological Findings in Short-Chain enoyl-CoA Hydratase 1 Deficiency (ECHS1D): Case Report and Differential Diagnosis.
    Eva Manuela Pena-Burgos, Rita María Regojo, Miguel Sáenz de Pipaón, Fernando Santos-Simarro, Pedro Ruiz-Sala, Belén Pérez, María Isabel Esteban-Rodríguez.
      Short-chain enoyl-CoA hydratase 1 (ECHS1) is an enzyme that participates in the metabolism of valine, transforming methacrylyl-CoA in β-hydroxy-isobutyryl-CoA. There is an accumulation of intermediate acids and ammonium as a consequence of its deficit. This background generates a harmful environment for the brain causing neuronal death and severe brain lesions. We present a case of a 39 weeks newborn that died at 31 hours old. We found vacuolization in basal areas, brain stem, cerebellum and spinal cord white matter (spongiform myelinopathy). These vacuoles were periodic acid-Schiff stain negative, there were neither acompanion gliosis nor macrophagic reaction. These findings were suggestive of metabolism acid disorders. The final diagnosis was confirmed by genetic study by massive parallel sequencing, showing 2 previously described pathogenic variants (c.160C > T and c.394G > A) of short-chain enoyl-CoA hydratase 1 gene. To our knowledge, this is the first case reporting the histological changes in short-chain enoyl-CoA hydratase 1 deficiency. Histological study provides useful information to orientate the diagnostic and clarify the clinical manifestations, especially in hospitals where urine or blood samples are not taking routinely or where genetic studies may not be performed.Synopsis: The main neuropathological findings in Short-chain enoyl-CoA hydratase 1 deficiency are the presence of whitte matter vacuoles in basal areas, brain stem and spinal cord.
    Keywords:  hypoxic–ischemic encephalopathy; inborn metabolism error; neuropathology; short-chain enoyl-CoA hydratase 1; vacuoles; whitte matter
    DOI:  https://doi.org/10.1177/10935266221134650
  22. J Pharmacol Exp Ther. 2022 Nov;383(2): 137-148
    Mitochondrial Dysfunction and Pharmacodynamics of Mitofusin Activation in Murine Charcot-Marie-Tooth Disease Type 2A.
    Antonietta Franco, Xiawei Dang, Lihong Zhang, Perry B Molinoff, Gerald W Dorn.
      Mitofusin (MFN) 1 and MFN2 are dynamin GTPase family mitochondrial proteins that mediate mitochondrial fusion requiring MFN conformational shifts, formation of macromolecular complexes on and between mitochondria, and GTP hydrolysis. Damaging MFN2 mutations cause an untreatable, largely pediatric progressive peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease type 2A. We used small molecule allosteric mitofusin activators that promote MFN conformations favoring fusion to interrogate the effects of MFN2 conformation and GTPase activity on MFN2-mediated mitochondrial fusion and motility in vitro. We translated these findings in vivo by defining dose-dependent pharmacodynamic and disease-modifying effects of mitofusin activators in murine CMT2A. MFN2 catalytic GTPase activity and MFN2 conformational switching are essential for mitochondrial fusion, but the two processes are separate and dissociable. We report the first concentration-response relationships for mitofusin activators to stimulate mitochondrial transport through CMT2A neuronal axons, which is similar to their stimulation of mitochondrial fusion. In CMT2A mice, intermittent (daily short acting) and sustained (twice daily long acting) mitofusin activation were equally effective in reversing neuromuscular degeneration. Moreover, acute dose-dependent pharmacodynamic effects of mitofusin activators on mitochondrial transport through CMT2A neuronal axons anticipated those for long-term reversal of neurodegenerative phenotypes. A crossover study showed that CMT2A neuronal deficits recurred after mitofusin activators are discontinued, and revealed that CMT2A can be ameliorated by mitofusin activation even in old (>74 week) mice. These data add to our understanding of mitochondrial dysfunction induced by a CMT2A MFN2 GTPase mutation and provide additional information supporting the approach of pharmacological mitofusin activation in CMT2A. SIGNIFICANCE: This study interrogated the roles of MFN2 catalytic activity and allosteric activation on impaired mitochondrial fusion and neuronal transport as they impact an untreatable peripheral neuropathy caused by MFN2 mutations, Charcot-Marie-Tooth disease type 2A. The results mechanistically link mitochondrial fusion and motility to the relaxed MFN2 protein conformation and correction of mitochondrial abnormalities to in vivo reversal of neurodegeneration in murine CMT2A.
    DOI:  https://doi.org/10.1124/jpet.122.001332
  23. Hum Mol Genet. 2022 Dec 15. pii: ddac297. [Epub ahead of print]
    Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway-implications for Parkinson's disease.
    Willcyn Tang, John Thundyil, Grace Gui Yin Lim, Teddy J W Tng, Sean Qing Zhang Yeow, Aditya Nair, Chou Chai, Tso-Pang Yao, Kah-Leong Lim.
      Abnormal lipid homeostasis has been observed in the brain of Parkinson's disease (PD) patients and experimental models, although the mechanism underlying this phenomenon is unclear. Notably, previous studies have reported that the PD-linked protein Parkin functionally interacts with important lipid regulators, including Sterol Regulatory Element Binding Proteins (SREBPs) and Cluster of differentiation 36 (CD36). Here, we demonstrate a functional relationship between Parkin and Lipoprotein Lipase (LPL), a triglyceride lipase that is widely expressed in the brain. Using a human neuroblastoma cell line and a Parkin knockout (KO) mouse model, we demonstrate that Parkin expression level positively correlates with neuronal LPL protein level and activity. Importantly, our study identified SREBP2, a major regulator of sterol and fatty acid synthesis, as a potential mediator between Parkin and LPL. Supporting this, SREBP2 genetic ablation abolished Parkin effect on LPL expression. We further demonstrate that Parkin-LPL pathway regulates the formation of intracellular lipid droplets, and that this pathway is upregulated upon exposure to PD-linked oxidative stress induced by rotenone. Finally, we show that inhibition of either LPL or SREBP2 exacerbates rotenone-induced cell death. Taken together, our findings reveal a novel pathway linking Parkin, SREBP2, and LPL in neuronal lipid homeostasis that may be relevant to the pathogenesis of PD.
    DOI:  https://doi.org/10.1093/hmg/ddac297
  24. J Clin Lipidol. 2022 Nov-Dec;16(6):pii: S1933-2874(22)00288-4. [Epub ahead of print]16(6): 887-894
    Ethyl EPA and ethyl DHA cause similar and differential changes in plasma lipid concentrations and lipid metabolism in subjects with low-grade chronic inflammation.
    Jisun So, Bela F Asztalos, Katalin Horvath, Stefania Lamon-Fava.
      BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to similarly lower plasma TG concentrations but differentially regulate plasma LDL-C and HDL-C concentrations.OBJECTIVE: The aim of this study was to evaluate the common and differential effects of these ω-3 fatty acids on plasma lipids and lipoproteins and to assess the metabolic mechanisms of the effects.
    METHODS: In a randomized, double-blind, crossover study, we assessed the effect of 10-week supplementation with 3 g/d pure EPA and pure DHA (both as ethyl ester, ≥97% purity) on plasma lipid and lipoprotein concentrations and activities of lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) in 21 older (>50 y) men and postmenopausal women with some characteristics of metabolic syndrome and low-grade chronic inflammation.
    RESULTS: Both EPA and DHA lowered plasma TG concentrations and increased LDL-C/apoB and HDL-C/apoA-I ratios, but only DHA increased LDL-C concentrations. The reductions in plasma TG were inversely associated with the changes in LPL activity after both EPA and DHA supplementation. EPA lowered CETP, while DHA lowered LCAT activity. EPA and DHA worked differently in men and women, with DHA increasing LPL activity and LDL-C concentrations in women, but not in men.
    CONCLUSIONS: EPA and DHA exerted similar effects on plasma TG, but differences were observed in LDL-C concentrations and activities of some enzymes involved in lipoprotein metabolism. It was also noted that EPA and DHA worked differently in men and women, supporting sex-specific variations in lipoprotein metabolism.
    Keywords:  Cholesterol; Cholesteryl ester transfer protein; Docosahexaenoic acid; Eicosapentaenoic acid; Lecithin cholesterol acyl transferase; Lipoprotein lipase; Omega-3 fatty acids; Triglycerides
    DOI:  https://doi.org/10.1016/j.jacl.2022.10.002
  25. Neurobiol Aging. 2022 Nov 17. pii: S0197-4580(22)00236-6. [Epub ahead of print]122 65-75
    Brain total creatine differs between primary progressive aphasia (PPA) subtypes and correlates with disease severity.
    Kathleen E Hupfeld, Helge J Zöllner, Georg Oeltzschner, Hayden W Hyatt, Olivia Herrmann, Jessica Gallegos, Steve C N Hui, Ashley D Harris, Richard A E Edden, Kyrana Tsapkini.
      Primary progressive aphasia (PPA) is comprised of three subtypes: logopenic (lvPPA), non-fluent (nfvPPA), and semantic (svPPA). We used magnetic resonance spectroscopy (MRS) to measure tissue-corrected metabolite levels in the left inferior frontal gyrus (IFG) and right sensorimotor cortex (SMC) from 61 PPA patients. We aimed to: (1) characterize subtype differences in metabolites; and (2) test for metabolite associations with symptom severity. tCr differed by subtype across the left IFG and right SMC. tCr levels were lowest in lvPPA and highest in svPPA. tCr levels predicted lvPPA versus svPPA diagnosis. Higher IFG tCr and lower Glx correlated with greater disease severity. As tCr is involved in brain energy metabolism, svPPA pathology might involve changes in specific cellular energy processes. Perturbations to cellular energy homeostasis in language areas may contribute to symptoms. Reduced cortical excitatory capacity (i.e. lower Glx) in language regions may also contribute to symptoms. Thus, tCr may be useful for differentiating between PPA subtypes, and both tCr and Glx might have utility in understanding PPA mechanisms and tracking progression.
    Keywords:  Creatine (tCr); Glutamate+glutamine (Glx); Magnetic resonance spectroscopy (MRS); Point RESolved Spectroscopy (PRESS); Primary Progressive Aphasia (PPA)
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.11.006
  26. Neuroscience. 2022 Dec 07. pii: S0306-4522(22)00603-0. [Epub ahead of print]
    Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy.
    Kai-Leng Tan, Han-Chung Lee, Pike-See Cheah, King-Hwa Ling.
      Mitochondrial dysfunctions have been described in Down syndrome (DS) caused by either partial or full trisomy of chromosome 21 (HSA21). Mitochondria play a crucial role in various vital functions in eukaryotic cells, especially in energy production, calcium homeostasis and programmed cell death. The function of mitochondria is primarily regulated by genes encoded in the mitochondrion and nucleus. Many genes on HSA21 are involved in oxidative phosphorylation (OXPHOS) and regulation of mitochondrial functions. This review highlights the HSA21 dosage-sensitive nuclear-encoded mitochondrial genes associated with overexpression-related phenotypes seen in DS. This includes impaired mitochondrial dynamics, structural defects and dysregulated bioenergetic profiles such as OXPHOS deficiency and reduced ATP production. Various therapeutic approaches for modulating energy deficits in DS, effects and molecular mechanism of gene therapy and drugs that exert protective effects through modulation of mitochondrial function and attenuation of oxidative stress in DS cells were discussed. It is prudent that improving DS pathophysiological conditions or quality of life may be feasible by targeting something as simple as cellular mitochondria biogenesis and function.
    Keywords:  Down syndrome; anaerobic glucose metabolism; energy metabolism; mitochondrial dysfunction; oxidative; phosphorylation; triomy 21
    DOI:  https://doi.org/10.1016/j.neuroscience.2022.12.003
  27. Cancers (Basel). 2022 Dec 05. pii: 5995. [Epub ahead of print]14(23):
    Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines.
    Ashok Panigrahy, Regina I Jakacki, Ian F Pollack, Rafael Ceschin, Hideho Okada, Marvin D Nelson, Gary Kohanbash, Girish Dhall, Stefan Bluml.
      PURPOSE: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression.METHODS: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline).
    RESULTS: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9-3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2-3 doses (3.9-5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67-0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11-0.63) and 0.26 (0.04-0.48) in the non-vaccine cohort.
    CONCLUSION: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study.
    Keywords:  MR spectroscopy; brainstem glioma; choline; creatine; immunotherapy; myo-inositol; pediatric brain tumor; vaccine therapy
    DOI:  https://doi.org/10.3390/cancers14235995
  28. Methods Mol Biol. 2023 ;2609 227-249
    Methods to Assess the Role of PARPs in Regulating Mitochondrial Oxidative Function.
    Tünde Kovács, Boglárka Rauch, Edit Mikó, Péter Bai.
      PARP enzymes are involved in metabolic regulation and impact on a plethora of cellular metabolic pathways, among them, mitochondrial oxidative metabolism. The detrimental effects of PARP1 overactivation upon oxidative stress on mitochondrial oxidative metabolism was discovered in 1998. Since then, there was an enormous blooming in the understanding of the interplay between PARPs and mitochondria. Mitochondrial activity can be assessed by a comprehensive set of methods that we aim to introduce here.
    Keywords:  ARTD; Differentiation; Flow cytometry; Mitochondria; Mitochondrial fission; Mitochondrial fusion; Mitochondrial morphology; Oximetry; PARP; Seahorse extracellular flux analyzer; Substrate preference; Δψ
    DOI:  https://doi.org/10.1007/978-1-0716-2891-1_14
  29. J Clin Med. 2022 Dec 01. pii: 7139. [Epub ahead of print]11(23):
    Associations between Fatty Acid Intake and Tension-Type Headache: A Cross-Sectional Study.
    Diego Domínguez-Balmaseda, José Ángel Del-Blanco-Muñiz, Angel González-de-la-Flor, Guillermo García-Pérez-de-Sevilla.
      INTRODUCTION: Patients with tension-type headache (TTH) are characterized by recurrent pain that can become disabling. Identifying the dietary triggers of headaches has led to defining dietary strategies to prevent this disease. In fact, excessive dietary intake of Omega-6 (ω-6) fatty acids, or an ω-6: ω3 ≥ 5 ratio, typical of Western diets, has been associated with a higher prevalence of headaches. The objectives of the present study were to compare dietary fatty acid intake between participants with and without chronic TTH and to investigate the association between dietary fatty acid intake, pain characteristics, and quality of life in patients with chronic TTH.METHODS: An observational study was conducted, comparing healthy participants (n = 24) and participants diagnosed with chronic TTH for more than six months (n = 24). The variables analyzed were dietary fatty acid intake variables, the Headache Impact Test (HIT-6), and the characteristics of the headache episodes (intensity, frequency, and duration).
    RESULTS: The TTH group reported a significantly higher intake of saturated fatty acids (SFAs) but similar intakes of monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and ω-6: ω-3 ratio when compared to controls. Furthermore, in the TTH group, the Ω-6 fatty acid intake was associated with more intense headache episodes. In addition, the TTH group reported a significant impact of headaches on their activities of daily living according to the HIT-6.
    CONCLUSIONS: Higher intakes of SFAs and Ω-6 fatty acids were associated with more severe headache episodes in patients with TTH. Therefore, the characteristics of the diet, in particular the dietary fatty acid intake, should be considered when treating these patients.
    Keywords:  Omega-3 (ω-3); Omega-6 (ω-6); monounsaturated fatty acids (MUFAs); polyunsaturated fatty acids (PUFAs); tension-type headache
    DOI:  https://doi.org/10.3390/jcm11237139
  30. Neurochem Int. 2022 Dec 09. pii: S0197-0186(22)00181-4. [Epub ahead of print] 105456
    Astrocyte innate immune activation and injury amplification following experimental focal cerebral ischemia.
    John Constantakis, Catherine A Reed-McBain, Bolanle Famakin.
      Astrocytes are a distinct population of glial cells responsible for many homeostatic functions in normal neural architecture. In the healthy brain, astrocyte functions range from maintenance of the blood brain barrier to modulation of synaptic transmission and neuronal plasticity to glial scar formation post-ischemic injury. In humans, this group of cells exhibits far greater heterogeneity than previously thought-with distinct subpopulations that likely carry out specialized functions. Following ischemic injury, astrocytes take on a distinct phenotype-known as the reactive astrocyte. This phenotype is responsible for both the propagation and amelioration of neuronal injury during ischemia. Following ischemia, astrocytes undergo temporal and spatial-dependent changes in morphology, gene expression, hypertrophy and hyperplasia as a result of signaling within the local microenvironment of the penumbra compared to the core infarct. This elicits a cascade of downstream effects, including inflammation and activation of the innate immune system, which both propagates and ameliorates local injury within the brain parenchyma. This review will focus upon the double-edged sword-that are astrocytes and the innate immune system. We will discuss the role that astrocytes and the innate immune system play in amplifying secondary brain injury, as well as attenuating ischemic damage. Specifically, we will focus on molecular signaling and processes that could be targeted as potential therapeutic interventions.
    Keywords:  Astrocytes; Cerebral ischemia; Glia; Innate immunity
    DOI:  https://doi.org/10.1016/j.neuint.2022.105456
  31. Metab Brain Dis. 2022 Dec 12.
    Free-L-Cysteine improves corticosterone-induced behavioral deficits, oxidative stress and neurotransmission in rats.
    Noreen Samad, Mikhba Rafeeque, Imran Imran.
      L-Cysteine (L-Cys) is a semi-essential amino acid. It serves as a substrate for enzyme cystathionine-β-synthase in the central nervous system (CNS). L-Cys showed various antioxidant characteristics. Though, studies on the effect of free L-Cys administration to evaluate the CNS functioning is very limited. Therefore, we assessed the effects of L-Cys on corticosterone (CORT) induced oxidative stress, behavioral deficits and memory impairment in male rats. L-Cys (150 mg/kg/ml) administered to vehicle and CORT (20 mg/kg/ml) treated rats orally for 28 days. Behavioral activities were conducted after treatment period. Subsequently, rats were sacrificed, blood and brain were removed. Hippocampus was isolated from brain and then hippocampus and plasma were collected for oxidative, biochemical and neurochemical analysis. Results showed that repeated treatment of L-Cys produced antidepressant, anxiolytic and memory-improving effects which may be ascribed to the enhanced antioxidant profile, normalized cholinergic, serotonergic neurotransmission in brain (hippocampus) following CORT administration. Increased plasma CORT by CORT administration was also normalized by L-Cys. The current study concluded that administration of free L-Cys improved the behavioral, biochemical, neurochemical and redox status of CNS. Hence, L-Cys could be protective therapeutic modulator against stress induced neurological ailments.
    Keywords:  Antioxidant enzyme; Behavioral deficits; Cholinergic function; Corticosterone; L-cysteine; Memory function; Oxidative stress; Serotonergic metabolism
    DOI:  https://doi.org/10.1007/s11011-022-01143-w
  32. Biochem Biophys Res Commun. 2022 Dec 01. pii: S0006-291X(22)01662-X. [Epub ahead of print]640 12-20
    Spatial and temporal alterations of developing oligodendrocytes induced by repeated sevoflurane exposure in neonatal mice.
    Zhihao Zhang, Huiqing Liu, Sansan Jia, Jianshuai Zhao, Jiajia Wang, Yang Liu, Fang Zhou, Qi Li, Zhaofei Li, Hailong Dong, Yi Zeng, Rui Zhang, Haixing Zhong.
      The general anesthesia associated with long-term cognitive impairment has been causing the concern of the whole society. In particular, repeated anesthetic exposures may affect executive function, processing speed, and fine motor skills, which all directly depended on the functions of oligodendrocytes, myelin, and axons. However, the underlying mechanisms are still largely unknown. To investigate the spatial and temporal alterations in oligodendrocytes in the corpus callosum (CC) and hippocampus following repeated sevoflurane exposures (3%, for 2 h) from postnatal day 6 (P6) to P8, we used immunofluorescence, Western blot, and a battery of behavioral tests. As previously stated, we confirmed that early anesthetic exposures hampered both cognitive and motor performance during puberty in the rotarod and banes tests. Intriguingly, we discovered that the proliferation of oligodendrocyte progenitor cells (OPCs) was immediately enhanced after general anesthesia in the CC and hippocampus from P8 to P32. From P8 through P15, the overall oligodendrocyte population remained constant. However, along with the structural myelin abnormalities, the matured oligodendrocytes statistically reduced in the CC (from P15) and hippocampus (from P32). Administration of clemastine, which could induce OPC differentiation and myelin formation, significantly increased matured oligodendrocytes and promoted myelination and cognition. Collectively, we first demonstrated the bi-directional influence of early sevoflurane exposures on oligodendrocyte maturation and proliferation, which contributes to the cognitive impairment induced by general anesthesia. These findings illustrated the dynamic changes in oligodendrocytes in the developing brain following anesthetic exposures, as well as possible therapeutic strategies for multiple general anesthesia associated cognitive impairment.
    Keywords:  Corpus callosum; Hippocampus; Neonatal; Neurotoxicity; Oligodendrocytes; Sevoflurane
    DOI:  https://doi.org/10.1016/j.bbrc.2022.11.105
  33. Environ Epigenet. 2022 ;8(1): dvac024
    Paternal transmission of behavioural and metabolic traits induced by postnatal stress to the 5th generation in mice.
    Chiara Boscardin, Francesca Manuella, Isabelle M Mansuy.
      Life experiences and environmental conditions in childhood can change the physiology and behaviour of exposed individuals and, in some cases, of their offspring. In rodent models, stress/trauma, poor diet, and endocrine disruptors in a parent have been shown to cause phenotypes in the direct progeny, suggesting intergenerational inheritance. A few models also examined transmission to further offspring and suggested transgenerational inheritance, but such multigenerational inheritance is not well characterized. Our previous work on a mouse model of early postnatal stress showed that behaviour and metabolism are altered in the offspring of exposed males up to the 4th generation in the patriline and up to the 2nd generation in the matriline. The present study examined if symptoms can be transmitted beyond the 4th generation in the patriline. Analyses of the 5th and 6th generations of mice revealed that altered risk-taking and glucose regulation caused by postnatal stress are still manifested in the 5th generation but are attenuated in the 6th generation. Some of the symptoms are expressed in both males and females, but some are sex-dependent and sometimes opposite. These results indicate that postnatal trauma can affect behaviour and metabolism over many generations, suggesting epigenetic mechanisms of transmission.
    Keywords:  5th and 6th generations; glucose metabolism; mouse model; offspring; patriline; postnatal trauma; risk-taking; transgenerational inheritance; weight
    DOI:  https://doi.org/10.1093/eep/dvac024
  34. Front Neurosci. 2022 ;16 1066528
    Integrated transcriptomic and metabolomic profiling reveals dysregulation of purine metabolism during the acute phase of spinal cord injury in rats.
    Zhong Zeng, Mei Li, Zhanfeng Jiang, Yuanxiang Lan, Lei Chen, Yanjun Chen, Hailiang Li, Jianwen Hui, Lijian Zhang, Xvlei Hu, Hechun Xia.
      Introduction: Spinal cord injury (SCI) results in drastic dysregulation of microenvironmental metabolism during the acute phase, which greatly affects neural recovery. A better insight into the potential molecular pathways of metabolic dysregulation by multi-omics analysis could help to reveal targets that promote nerve repair and regeneration in the future.Materials and methods: We established the SCI model and rats were randomly divided into two groups: the acute-phase SCI (ASCI) group (n = 14, 3 days post-SCI) and the sham group with day-matched periods (n = 14, without SCI). In each group, rats were sacrificed at 3 days post-surgery for histology study (n = 3), metabolome sequencing (n = 5), transcriptome sequencing (n = 3), and quantitative real-time polymerase chain reaction (n = 3). The motor function of rats was evaluated by double-blind Basso, Beattie, and Bresnahan (BBB) Locomotor Scores at 0, 1, 2, 3 days post-SCI in an open field area. Then the transcriptomic and metabolomic data were integrated in SCI model of rat to reveal the underlying molecular pathways of microenvironmental metabolic dysregulation.
    Results: The histology of the microenvironment was significantly altered in ASCI and the locomotor function was significantly reduced in rats. Metabolomics analysis showed that 360 metabolites were highly altered during the acute phase of SCI, of which 310 were up-regulated and 50 were down-regulated, and bioinformatics analysis revealed that these differential metabolites were mainly enriched in arginine and proline metabolism, D-glutamine and D-glutamate metabolism, purine metabolism, biosynthesis of unsaturated fatty acids. Transcriptomics results showed that 5,963 genes were clearly altered, of which 2,848 genes were up-regulated and 3,115 genes were down-regulated, and these differentially expressed genes were mainly involved in response to stimulus, metabolic process, immune system process. Surprisingly, the Integrative analysis revealed significant dysregulation of purine metabolism at both transcriptome and metabolome levels in the acute phase of SCI, with 48 differential genes and 16 differential metabolites involved. Further analysis indicated that dysregulation of purine metabolism could seriously affect the energy metabolism of the injured microenvironment and increase oxidative stress as well as other responses detrimental to nerve repair and regeneration.
    Discussion: On the whole, we have for the first time combined transcriptomics and metabolomics to systematically analyze the potential molecular pathways of metabolic dysregulation in the acute phase of SCI, which will contribute to broaden our understanding of the sophisticated molecular mechanisms of SCI, in parallel with serving as a foundation for future studies of neural repair and regeneration after SCI.
    Keywords:  integrated analysis; metabolomics; purine metabolism; spinal cord injury; transcriptomics
    DOI:  https://doi.org/10.3389/fnins.2022.1066528
  35. Adv Exp Med Biol. 2022 ;1395 65-68
    Postnatal Exposure to Brief Hypoxia Alters Brain VEGF Expression and Capillary Density in Adult Mice.
    Michael B Komarovsky, Constantinos P Tsipis, Khalil A Almotah, Walter F Boron, Kui Xu, Joseph LaManna.
      Perinatal hypoxia leads to changes in cerebral angiogenesis and persistent structural and functional changes in the adult brain. It may also result in greater vulnerability to subsequent challenges. We investigated the effect of postnatal day 2 (P2) hypoxic preconditioning on adult brain capillary density and brain vascular endothelial growth factor (VEGF) expression in mice. P2 mice were exposed to hypoxia (5% O2) in a normobaric chamber for 2 h then returned to normoxia while their littermates remained in normoxia (P2 control). After 2-6 months, they were euthanised and their brains were removed for capillary density determination. Another set of animals (P2 hypoxic mice and P2 controls) were euthanised at 2, 10, 23, and 60 days after birth and brain VEGF expression was assessed by western blot. Adult brain capillary density was significantly increased in the P2 hypoxic mice when compared to the P2 control mice. Additionally, VEGF expression appeared to be elevated in the P2-hypoxia mice when compared to the P2-control mice at all time points, and VEGF levels in P2-hypoxia mice declined with age similarly to P2-control mice. These data demonstrate that transient early-postnatal hypoxic stress leads to an increase in capillary density that persists in the adult, possibly due to increased VEGF expression. These results might be explained by epigenetic factors in the VEGF gene.
    Keywords:  Epigenetics; Hypoxic preconditioning; Perinatal hypoxia; Postnatal hypoxic stress
    DOI:  https://doi.org/10.1007/978-3-031-14190-4_11
  36. Dis Model Mech. 2022 Dec 01. pii: dmm049843. [Epub ahead of print]15(12):
    Sterol dysregulation in Smith-Lemli-Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk.
    Bethany A Freel, Benjamin A Kelvington, Sonali Sengupta, Malini Mukherjee, Kevin R Francis.
      Owing to the need for de novo cholesterol synthesis and cholesterol-enriched structures within the nervous system, cholesterol homeostasis is critical to neurodevelopment. Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith-Lemli-Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte-microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte-microglia immune axis, with possible implications in other neurological diseases.
    Keywords:   Dhcr7 ; Astrocyte; Cholesterol; Microglia; Reactivity; Smith–Lemli–Opitz syndrome
    DOI:  https://doi.org/10.1242/dmm.049843
  37. Int J Mol Sci. 2022 Nov 25. pii: 14749. [Epub ahead of print]23(23):
    Acid Sphingomyelinase Inhibitor, Imipramine, Reduces Hippocampal Neuronal Death after Traumatic Brain Injury.
    Si Hyun Lee, A Ra Kho, Song Hee Lee, Dae Ki Hong, Beom Seok Kang, Min Kyu Park, Chang Juhn Lee, Hyun Wook Yang, Seo Young Woo, Se Wan Park, Dong Yeon Kim, Bo Young Choi, Sang Won Suh.
      Traumatic brain injury (TBI) broadly degrades the normal function of the brain after a bump, blow, or jolt to the head. TBI leads to the aggravation of pre-existing brain dysfunction and promotes neurotoxic cascades that involve processes such as oxidative stress, loss of dendritic arborization, and zinc accumulation. Acid sphingomyelinase (ASMase) is an enzyme that hydrolyzes sphingomyelin to ceramide in cells. Under normal conditions, ceramide plays an important role in various physiological functions, such as differentiation and apoptosis. However, under pathological conditions, excessive ceramide production is toxic and activates the neuronal-death pathway. Therefore, we hypothesized that the inhibition of ASMase activity by imipramine would reduce ceramide formation and thus prevent TBI-induced neuronal death. To test our hypothesis, an ASMase inhibitor, imipramine (10 mg/kg, i.p.), was administrated to rats immediately after TBI. Based on the results of this study, we confirmed that imipramine significantly reduced ceramide formation, dendritic loss, oxidative stress, and neuronal death in the TBI-imipramine group compared with the TBI-vehicle group. Additionally, we validated that imipramine prevented TBI-induced cognitive dysfunction and the modified neurological severity score. Consequently, we suggest that ASMase inhibition may be a promising therapeutic strategy to reduce hippocampal neuronal death after TBI.
    Keywords:  acid sphingomyelinase; ceramide; imipramine; neuronal death; traumatic brain injury
    DOI:  https://doi.org/10.3390/ijms232314749
  38. Nutrients. 2022 Nov 23. pii: 4977. [Epub ahead of print]14(23):
    Ketogenic Diets in the Management of Lennox-Gastaut Syndrome-Review of Literature.
    Urszula Skrobas, Piotr Duda, Łukasz Bryliński, Paulina Drożak, Magdalena Pelczar, Konrad Rejdak.
      Epilepsy is an important medical problem with approximately 50 million patients globally. No more than 70% of epileptic patients will achieve seizure control after antiepileptic drugs, and several epileptic syndromes, including Lennox-Gastaut syndrome (LGS), are predisposed to more frequent pharmacoresistance. Ketogenic dietary therapies (KDTs) are a form of non-pharmacological treatments used in attempts to provide seizure control for LGS patients who experience pharmacoresistance. Our review aimed to evaluate the efficacy and practicalities concerning the use of KDTs in LGS. In general, KDTs are diets rich in fat and low in carbohydrates that put the organism into the state of ketosis. A classic ketogenic diet (cKD) is the best-evaluated KDT, while alternative KDTs, such as the medium-chain triglyceride diet (MCT), modified Atkins diet (MAD), and low glycemic index treatment (LGIT) present several advantages due to their better tolerability and easier administration. The literature reports regarding LGS suggest that KDTs can provide ≥50% seizure reduction and seizure-free status in a considerable percentage of the patients. The most commonly reported adverse effects are constipation, diarrhea, and vomiting, while severe adverse effects such as nephrolithiasis or osteopenia are rarely reported. The literature review suggests that KDTs can be applied safely and are effective in LGS treatment.
    Keywords:  Lennox-Gastaut syndrome; diet therapy; epilepsy; epileptic syndromes; ketogenic diets
    DOI:  https://doi.org/10.3390/nu14234977
  39. Stem Cell Res. 2022 Dec 07. pii: S1873-5061(22)00346-4. [Epub ahead of print]66 102997
    Generation of an induced pluripotent stem cell line (SHCDNi007-A) from a patient with pyruvate carboxylase deficiency carrying compound heterozygous (c.182 T > C/ c.2581G > A) variants in PC.
    Jingjing Sun, Pei Lu, Yunlin Shen, Li Ma.
      Pyruvate carboxylase (PC) deficiency (PCD), due to biallelic PC variants, is a rare inherited metabolic disease, which is characterized by seizures, global developmental delay, as well as lactic acidosis, and elevated plasma pyruvate and alanine levels in affected individuals. In the present study, a new induced pluripotent stem cell line (SHCDNi007-A) was generated from the peripheral blood mononuclear cells of a 2-month-old male infant with biallelic PC mutations c.(182 T > C;2581G > A), i.e. p.(Ile61Thr;Val861Met). This cell line is expected to facilitate the in vitro modeling of the disease pathophysiology and the development of future therapeutics for PCD.
    DOI:  https://doi.org/10.1016/j.scr.2022.102997
  40. J Inflamm Res. 2022 ;15 6569-6580
    Lipidomics Changes in a Murine Model of Neuropsychiatric Lupus.
    Yihan Wang, Yating Ren, Tao Hong, Dingqi Lu, Fan Zhang, Yi Cao, Xinchang Wang.
      Purpose: Neuropsychiatric lupus (NPSLE) is one of the important manifestations of systemic lupus erythematosus. Previous studies mainly focused on the disruption of the blood-brain barrier and the production of brain-reactive autoantibodies, However, there is no comprehensive lipidomic analysis in NPSLE. Therefore, this research evaluated the lipidomic analysis in the hippocampus and liver of NPSLE mice with mood disorders, to explore the influence of the liver-brain axis on this disease.Methods: MRL/lpr mice and MRL/mpj mice were respectively used as NPSLE and control groups. Behavioral tests and systemic disease characteristics of mice were assessed at the age of 18 weeks. Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) was used for lipid metabolite determination. Multivariate statistical analysis was used to identify lipid metabolites that were differentially expressed in two groups.
    Results: Our results showed that 355 and 405 lipid metabolites were differentially expressed between the NPSLE and control groups in the hippocampus and liver. According to the pathway enrichment analysis, several pathways were affected, and the glycerophospholipid metabolism pathway was most relevant to the mouse's depressive behavior.
    Conclusion: Based on UPLC-MS/MS, the results provide evidence for how the liver-brain axis affects NPSLE and improve the understanding of NPSLE pathogenesis.
    Keywords:  depressive behavior; hippocampus; liver-brain axis; neuropsychiatric systemic lupus erythematosus
    DOI:  https://doi.org/10.2147/JIR.S391595
  41. Front Neurosci. 2022 ;16 1025108
    Short-term high-fat diet alters the mouse brain magnetic resonance imaging parameters consistently with neuroinflammation on males and metabolic rearrangements on females. A pre-clinical study with an optimized selection of linear mixed-effects models.
    Basilio Willem Campillo, David Galguera, Sebastian Cerdan, Pilar López-Larrubia, Blanca Lizarbe.
      Introduction: High-fat diet (HFD) consumption is known to trigger an inflammatory response in the brain that prompts the dysregulation of energy balance, leads to insulin and leptin resistance, and ultimately obesity. Obesity, at the same, has been related to cerebral magnetic resonance imaging (MRI) alterations, but the onset of HFD-induced neuroinflammation, however, has been principally reported on male rodents and by ex vivo methods, with the effects on females and the origin of MRI changes remaining unassessed.Methods: We characterized the onset and evolution of obesity on male and female mice during standard or HFD administration by physiological markers and multiparametric MRI on four cerebral regions involved in appetite regulation and energy homeostasis. We investigated the effects of diet, time under diet, brain region and sex by identifying their significant contributions to sequential linear mixed-effects models, and obtained their regional neurochemical profiles by high-resolution magic angle spinning spectroscopy.
    Results: Male mice developed an obese phenotype paralleled by fast increases in magnetization transfer ratio values, while females delayed the obesity progress and showed no MRI-signs of cerebral inflammation, but larger metabolic rearrangements on the neurochemical profile.
    Discussion: Our study reveals early MRI-detectable changes compatible with the development of HFD-induced cerebral cytotoxic inflammation on males but suggest the existence of compensatory metabolic adaptations on females that preclude the corresponding detection of MRI alterations.
    Keywords:  HRMAS; MRI; brain; high-fat diet; inflammation; mixed-effects models; obesity; sexual dimorphism
    DOI:  https://doi.org/10.3389/fnins.2022.1025108
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