25-Hydroxycholesterol modulates synaptic vesicle endocytosis at the mouse neuromuscular junction

Pflügers Archiv - European Journal of Physiology, Год журнала: 2025, Номер 477(3), С. 421 - 439

Опубликована: Янв. 9, 2025

Язык: Английский

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A unified model of the biology of peripartum depression

Translational Psychiatry, Год журнала: 2023, Номер 13(1)

Опубликована: Апрель 28, 2023

Abstract Peripartum depression (PPD) is a prevalent and debilitating disorder that adversely affects the development of mothers infants. Recently, there has been plea for increased mental health screening during peripartum period; however, currently, no accurate tool to identify women at risk PPD. In addition, some do not respond current treatment schemes develop treatment-resistant depression. The perspective aims propose unified understanding biological underpinnings PPD (UmPPD) considers heterogeneity in onset, symptoms cluster, severity Such model could promote basic applied research on suggest new avenues. central hub kynurenine pathway (KP) KP-serotonin ratio. forces specific processes play cause an imbalance within KP between serotonin are inflammation, stress, reproductive hormones (especially estradiol progesterone), oxytocin. UmPPD predicts most severe would comprise prolonged ongoing or multiple stressors, excessive estrogen, progesterone resistance, avoidance breastfeeding, skin-to-skin contact, social proximity. These factors be associated with higher likelihood developing PPD, early more significant symptom severity. subtypes consist different compositions expressions these components, one common factor. aid directing future possibly detecting critical help discover, develop, utilize novel treatments

Язык: Английский

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Dynamic Brain Lipid Profiles Modulate Microglial Lipid Droplet Accumulation and Inflammation Under Ischemic Conditions in Mice

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Сен. 9, 2024

Abstract Microglia are critically involved in post‐stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation microglia results a dysfunctional and pro‐inflammatory state the aged brain worsens outcome of neuroinflammatory neurodegenerative diseases. However, role LD‐rich (LDRM) under stroke conditions is unknown. Using vitro vivo models, herein patterns microglial LD their corresponding inflammatory signaling cascades studied. Interactions between temporal spatial dynamics lipid profiles phenotypes different regions found. Hence, display enhanced levels elevated perilipin 2 (PLIN2) expression when exposed to hypoxia or stroke. Such LDRM exhibit high TNF‐α, IL‐6, IL‐1β as well phenotype differentially expressed metabolism‐related genes. These post‐ischemic alterations result distinct with dynamics, especially regard cholesteryl ester triacylglycerol levels, further exacerbating inflammation. The present study sheds new light on dynamic changes aggregation ischemia, demonstrating mutual mechanism function, which contributes progression injury.

Язык: Английский

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A single-cell compendium of human cerebrospinal fluid identifies disease-associated immune cell populations

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(1)

Опубликована: Янв. 1, 2025

Single-cell transcriptomics applied to cerebrospinal fluid (CSF) for elucidating the pathophysiology of neurologic diseases has produced only a preliminary characterization CSF immune cells. derives from and borders central nervous system (CNS) tissue, allowing comprehensive accounting cell types along with their relative abundance immunologic profiles relevant CNS diseases. Using integration techniques publicly available datasets in combination our own studies, we generated compendium 139 subjects encompassing 135 58 blood samples. Healthy individuals across wide range diseases, such as multiple sclerosis (MS), Alzheimer's disease, Parkinson's COVID-19, autoimmune encephalitis, were included. We found differences lymphocyte myeloid subset frequencies different well distribution between CSF. identified what believe be new AREG+ dendritic cells exclusive that was more abundant MS compared healthy controls. Finally, transcriptional states microglia-like lymphoid subsets elucidated. Altogether, have created reference single-cell profiling useful scientific community future studies on

Язык: Английский

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Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(10), С. 9022 - 9022

Опубликована: Май 19, 2023

Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations RNA-binding protein FUS are one the common genetic reasons ALS accompanied by a ‘dying back’ type degeneration. Using fluorescent approaches microelectrode recordings, early structural functional alterations in diaphragm neuromuscular junctions (NMJs) were studied mutant mice at pre-onset stage. Lipid peroxidation decreased staining with lipid raft marker found mice. Despite preservation end-plate structure, immunolabeling revealed an increase levels presynaptic proteins, SNAP-25 synapsin 1. The latter can restrain Ca2+-dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation its recovery after tetanus compensatory endocytosis markedly depressed There was trend to attenuation axonal [Ca2+]in 20 Hz. However, no changes intraterminal Ca2+ transient response low frequency or quantal content synchrony external detected. At later stage, shrinking fragmentation end plates together decrease expression disturbance timing occurred. Overall, suppression exo–endocytosis activity probably due membrane properties, 1 kinetics could be sign nascent NMJ pathology, which leads contact disorganization.

Язык: Английский

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Metabolomic analysis of rat arterial serum under hypobaric hypoxia: Adaptive regulation of physiological systems by metabolic reprogramming

Biochemistry and Biophysics Reports, Год журнала: 2025, Номер 41, С. 101943 - 101943

Опубликована: Фев. 18, 2025

Язык: Английский

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A review of the putative antiseizure and antiepileptogenic mechanisms of action for soticlestat

Epilepsia, Год журнала: 2025, Номер unknown

Опубликована: Фев. 18, 2025

Abstract Soticlestat (TAK‐935) is a potent and selective inhibitor of cholesterol 24‐hydroxylase (CYP46A1), an enzyme primarily expressed in the brain that catabolizes to 24 S ‐hydroxycholesterol (24HC). In ELEKTRA phase II clinical trial, soticlestat reduced seizure frequency patients with developmental epileptic encephalopathies, two III studies evaluating safety efficacy Dravet syndrome (SKYLINE) Lennox–Gastaut (SKYWAY) have recently been completed. The exact mechanism action by which exerts pharmacological benefits remains undetermined. this review, we assess available preclinical evidence present working hypothesis for antiseizure effects soticlestat. data support three potential mechanisms action: (1) normalization threshold via reduction 24HC levels brain; as acts positive allosteric modulator glutamate N‐methyl‐D‐aspartate receptors, may lead decreased hyperexcitability elevated thresholds; (2) restoration sequestration from synaptic cleft; accumulation cleft enhances neural excitation can contribute neurotoxicity; inhibit conversion membrane lipid raft microdomain help preserve it, consequently reducing excessive excitation; (3) suppression neuroinflammation inflammatory cytokine release. These warrant further investigation.

Язык: Английский

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Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation

Journal of Xenobiotics, Год журнала: 2025, Номер 15(2), С. 44 - 44

Опубликована: Март 14, 2025

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and progression of neurodegenerative diseases. The brain’s complex architecture, composed interconnected cell types receptors, drives unique neuronal signaling pathways, modulates enzyme functions, leads to distinct CYP gene expression regulation patterns compared liver. Despite their relatively low levels expression, CYPs exert significant influence on responses, neurotoxin susceptibility, behavior, neurological disease risk. These are essential maintaining homeostasis, mediating cholesterol turnover, synthesizing metabolizing neurochemicals, neurosteroids, neurotransmitters. Moreover, they key participants oxidative stress neuroprotection, inflammation. In addition roles psychotropic drugs, substances abuse, endogenous compounds, impact efficacy, safety, resistance, underscoring importance beyond traditional metabolism. Their involvement critical physiological processes also links them onset Understanding cerebral is vital advancing neuroprotective strategies, personalizing treatments disorders, developing CNS-targeting therapeutics. This review explores emerging enzymes, particularly those within CYP1–3 CYP46 families, highlighting functional diversity pathological consequences dysregulation health. It examines potential CYP-based biomarkers improve diagnosis treatment offering new avenues therapeutic innovation.

Язык: Английский

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25-Hydroxycholesterol as a negative regulator of diaphragm muscle contractions via estrogen receptor and Ca2+ -dependent pathway

Histochemistry and Cell Biology, Год журнала: 2025, Номер 163(1)

Опубликована: Апрель 3, 2025

Язык: Английский

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Is reverse cholesterol transport regulated by active cholesterol?

Journal of Lipid Research, Год журнала: 2023, Номер 64(6), С. 100385 - 100385

Опубликована: Май 10, 2023

This review considers the hypothesis that a small portion of plasma membrane cholesterol regulates reverse transport in coordination with overall cellular homeostasis. It appears almost all is held stoichiometric complexes bilayer phospholipids. The minor fraction exceeds complexation capacity phospholipids called active cholesterol. has an elevated chemical activity and circulates among organelles. also moves down its gradient to HDL, facilitated by ABCA1, ABCG1, SR-BI. ABCA1 initiates this process perturbing organization bilayer, thereby priming for translocation apoA-I form nascent HDL. excess sterol activated itself follow ABCG1 similarly rearranges sends additional while SR-BI simply facilitates equilibration between membranes proteins. Active flows downhill cytoplasmic where it serves both as feedback signal homeostatic ER proteins substrate synthesis mitochondrial 27-hydroxycholesterol (27HC). 27HC binds LXR promotes expression aforementioned 27HC-LXR activates competitively displacing inhibitor, unliganded LXR. § Considerable indirect evidence suggests transport. Direct tests novel are proposed.

Язык: Английский

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