Neurosteroid enantiomers as potentially novel neurotherapeutics

Neuroscience & Biobehavioral Reviews, Год журнала: 2023, Номер 149, С. 105191 - 105191

Опубликована: Апрель 20, 2023

Endogenous neurosteroids and synthetic neuroactive steroids (NAS) are important targets for therapeutic development in neuropsychiatric disorders. These modulate major signaling systems the brain intracellular processes including inflammation, cellular stress autophagy. In this review, we describe studies performed using unnatural enantiomers of key neurosteroids, which physiochemically identical to their natural counterparts except rotation polarized light. led insights how NAS interact with receptors, ion channels sites action. Certain effects show high enantioselectivity, consistent actions chiral environments likely direct interactions proteins. Other no enantioselectivity even reverse enantioselectivity. The spectrum raises possibility that these agents, once considered only as tools preclinical studies, have potential complements some cases may exceed counterparts. Here review from perspective novel neurotherapeutics.

Язык: Английский

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Expression and function of estrogen receptors and estrogen-related receptors in the brain and their association with Alzheimer’s disease

Frontiers in Endocrinology, Год журнала: 2023, Номер 14

Опубликована: Июль 4, 2023

While estrogens are well known for their pivotal role in the female reproductive system, they also play a crucial function regulating physiological processes associated with learning and memory brain. Moreover, have neuroprotective effects pathogenesis of Alzheimer's disease (AD). Importantly, AD has higher incidence older postmenopausal women than men, estrogen treatment might reduce risk these women. In general, bind to activate receptors (ERs)-mediated transcriptional machineries, stimulate signal transduction through membrane ERs (mERs). Estrogen-related (ERRs), which share homologous sequences but lack estrogen-binding capabilities, widely highly expressed human brain been implicated pathogenesis. this review, we primarily provide summary ER ERR expression patterns addition, summarize recent studies on memory. We then review discuss research that elucidated functions importance ERRs pathogenesis, including Aβ clearance reduction phosphorylated tau levels. Elucidation mechanisms underlying ER- ERR-mediated machineries healthy diseased brains would new perspectives diagnosis AD. Furthermore, exploring potential receptors, ERs, will facilitate better understanding sex differences observed AD, lead novel sex-specific therapeutic approaches.

Язык: Английский

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Neuroactive metabolites and bile acids are altered in extremely premature infants with brain injury

Cell Reports Medicine, Год журнала: 2024, Номер 5(4), С. 101480 - 101480

Опубликована: Март 22, 2024

The gut microbiome is associated with pathological neurophysiological evolvement in extremely premature infants suffering from brain injury. exact underlying mechanism and its metabolic signatures are not fully understood. To decipher metabolite profiles linked to neonatal injury, we investigate the fecal plasma metabolome of samples obtained a cohort 51 at several time points, using liquid chromatography (LC)-high-resolution mass spectrometry (MS)-based untargeted metabolomics LC-MS/MS-based targeted analysis for investigating bile acids amidated acid conjugates. data integrated 16S rRNA gene amplicon as well patient cytokine, growth factor, T cell profiles. We find an early onset differentiation neuroactive metabolites between without detect bacterially derived amino conjugates feces. These results provide insights into early-life infants.

Язык: Английский

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Estrogen sulfotransferase and sulfatase in steroid homeostasis, metabolic disease, and cancer

Steroids, Год журнала: 2023, Номер 201, С. 109335 - 109335

Опубликована: Ноя. 10, 2023

Язык: Английский

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Rat Hair Metabolomics Analysis Reveals Perturbations of Unsaturated Fatty Acid Biosynthesis, Phenylalanine, and Arachidonic Acid Metabolism Pathways Are Associated with Amyloid-β-Induced Cognitive Deficits

Molecular Neurobiology, Год журнала: 2023, Номер 60(8), С. 4373 - 4395

Опубликована: Апрель 25, 2023

Abstract Hair is a noninvasive valuable biospecimen for the long-term assessment of endogenous metabolic disturbance. Whether hair suitable identifying biomarkers Alzheimer’s disease (AD) process remains unknown. We aim to investigate metabolism changes in after β-amyloid (Aβ 1-42 ) exposure rats using ultra-high-performance liquid chromatography-high-resolution mass spectrometry–based untargeted and targeted methods. Thirty-five days Aβ induction, displayed significant cognitive deficits, forty metabolites were changed, which twenty belonged three perturbed pathways: (1) phenylalanine phenylalanine, tyrosine, tryptophan biosynthesis— l -phenylalanine, phenylpyruvate, ortho-hydroxyphenylacetic acid, phenyllactic acid are up-regulated; (2) arachidonic (ARA) metabolism—leukotriene B4 (LTB4), arachidonyl carnitine, 5(S)-HPETE upregulation, but ARA, 14,15-DiHETrE, 5(S)-HETE, PGB2 opposite; (3) unsaturated fatty eicosapentaenoic (EPA), docosahexaenoic (DHA), FA 18:3 + 1O, 2O downregulated. Linoleic belonging biosynthesis includes upregulation 8-hydroxy-9,10-epoxystearic 13-oxoODE, 18:2 4O, downregulation 9(S)-HPODE dihomo-γ-linolenic acid. In addition, cortisone dehydroepiandrosterone steroid hormone upregulated. These pathways also correlate with impairment stimulation. Furthermore, DHA, EPA, have been previously implicated cerebrospinal fluid AD patients show similar changing trend rats’ hair. data suggest can be useful that well reflects expression non-polar molecules under stimulation, five potential serve as novel biomarkers.

Язык: Английский

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Navigating the neurological frontier: Macromolecular marvels in overcoming blood-brain barrier challenges for advanced drug delivery

Heliyon, Год журнала: 2024, Номер 10(15), С. e35562 - e35562

Опубликована: Авг. 1, 2024

The blood-brain interface poses formidable obstacles in addressing neurological conditions such as Alzheimer's, Multiple Sclerosis, brain cancers, and cerebrovascular accidents. Serving a safeguard against potential threats the blood, this barrier hinders direct drug delivery to affected cells, necessitating specialized transport mechanisms. Within realm of nanotechnology, creation nanoscale carriers, including macromolecules polymers, lipids, metallic nanoparticles, is gaining prominence. These tailored diverse forms sizes enriched with specific functional groups for enhanced penetration targeting, are capturing growing interest. This revised abstract explores macromolecular dimension understanding how nanoparticles interact barrier. It re-evaluates structure function barrier, highlighting nanocarriers utilized brain. discussion delves into intricate pathways through which drugs navigate emphasizing distinctive attributes nanocarriers. Additionally, it recent innovations nanotechnology unconventional approaches delivery. Ultimately, paper addresses intricacies considerations developing macromolecular-based nanomedicines brain, aiming advance evolution ailments.

Язык: Английский

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Identification of a multi-omics factor predictive of long COVID in the IMPACC study

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 14, 2025

Following SARS-CoV-2 infection, ∼10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings LC could identify therapeutic opportunities. We utilized machine learning methods on analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized IMPACC cohort to a multi-omics "recovery factor". participants who experienced had lower recovery factor scores compared without LC. Biologic characterization revealed increased levels plasma proteins associated with inflammation, elevated transcriptional signatures heme metabolism, decreased androgenic steroids patients. The was also altered circulating immune cell frequencies. Notably, were predictive occurrence as early admission, irrespective acute disease severity. Thus, identifies risk infection reveals biomarkers potential treatment targets.

Язык: Английский

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Unraveling the Metabolic and Microbiome Signatures in Fecal Samples of Pregnant Women with Prenatal Depression

Metabolites, Год журнала: 2025, Номер 15(3), С. 179 - 179

Опубликована: Март 6, 2025

Background/Objectives: Prenatal depression (PND) poses a significant threat to the health of both mother and developing fetus. Despite its increasing prevalence, pathophysiology PND is not yet fully elucidated. Methods: In this study, we aimed investigate fecal metabolites gut microbiota in patients compared healthy controls explore potential correlations between these factors. Results: Through untargeted metabolomics analysis, identified 75 significantly altered patients, which 27 were structurally annotated implicated key pathways, such as linoleic acid metabolism phenylalanine, tyrosine, tryptophan biosynthesis. Notably, two Clostridia-associated enterobacteria, unclassified_c_Clostridia unclassified_f_Lachnospiraceae, enriched group, positively correlated with tyrosine negatively multiple sulfated neurosteroids. Conclusions: Our findings underscore robust association dysbiosis metabolic disturbances PND, specific alterations noted metabolism, neurosteroid homeostasis, pathways. These dysregulated metabolites-tyrosine, neurosteroids, acid-may serve diagnostic biomarkers therapeutic targets. Moreover, their interplay provides new insights into pathophysiological mechanisms particularly highlighting role gut-brain axis signaling neuroendocrine dysregulation inflammatory responses. However, further large-scale studies animal models are required validate detailed mechanistic

Язык: Английский

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Cholesterol Sulfate: Pathophysiological Implications and Potential Therapeutics

Biomolecules, Год журнала: 2025, Номер 15(5), С. 646 - 646

Опубликована: Апрель 30, 2025

Cholesterol sulfate (CS) is a naturally occurring cholesterol derivative that widely distributed across various tissues and body fluids. In humans, its biosynthesis primarily mediated by the sulfotransferase (SULT) 2B1b (SULT2B1b). Over years, CS has been found to play critical roles in physiological processes, including epidermal cell adhesion, sperm capacitation, platelet coagulation, glucolipid metabolism, bone gut microbiota neurosteroid biosynthesis, T-cell receptor signaling, immune migration. this review, we first introduce endogenous regulation of metabolism. We then highlight current advances understanding CS. Finally, delve into implications diseases, with particular focus on mechanism action potential therapeutic applications. A comprehensive CS’s function, regulation, role as disease modifier offers novel insights could pave way for innovative strategies targeting wide range conditions.

Язык: Английский

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X‐linked ichthyosis: New insights into a multi‐system disorder

Skin Health and Disease, Год журнала: 2022, Номер 2(4)

Опубликована: Окт. 17, 2022

Abstract Background X‐linked ichthyosis (XLI) is a rare genetic condition almostexclusively affecting males; it characterised by abnormal desquamation and retentionhyperkeratosis, presents with polygonal brown scales. Most cases resultfrom deletions within Xp22.31 spanning the STS (steroid sulfatase)gene, remaining resulting from STS‐specific mutations. For manyyears has been recognised that individuals XLI are at increased risk ofcryptorchidism corneal opacities. Methods We discuss emerging evidence such alsomore likely to be affected range of neurodevelopmental psychiatrictraits, cardiac arrhythmias, fibrotic bleeding‐relatedconditions. consider candidate mechanisms may confer elevatedlikelihood these individual conditions, propose novel commonbiological pathway. Results Understanding prevalence, nature co‐occurrence ofcomorbidities associated critical for ensuring early identificationof symptoms providing most effective counselling andmultidisciplinary care individuals. Conclusion Future work in males XLI, new preclinical andcellular model systems, should further clarify underlying pathophysiologicalmechanisms amenable therapeutic intervention.

Язык: Английский

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