Marine sterols from brown seaweeds, particularly fucosterol and its oxidized derivative saringosterol, have shown therapeutic potential for Alzheimer’s disease (AD) and cardiovascular diseases. Here, we aimed to elucidate the cellular and in vivo mechanisms underlying their beneficial effects. In human HepG2 hepatocytes and CCF-STTG1 astrocytoma cells, we assessed liver x receptor (LXRα /LXRβ) activation, sterol uptake, and effects on cholesterol metabolism using luciferase reporter assays, GC–MS sterol profiling, and 13 C-acetate incorporation. In THP-1–derived macrophages, we evaluated sterol-induced cholesterol efflux using radiolabeled [ 3 H]-cholesterol assays and characterized anti-inflammatory responses by quantifying lipopolysaccharide (LPS) -induced cytokine production. Wild-type C57BL/6J mice were fed diets enriched with either fucosterol (0.2% w/w) or saringosterol (0.02% w/w) for 7 days, after which sterol profiles in serum, liver, and brain were quantified by GC–MS. Hippocampal transcriptional responses were assessed by RNA sequencing. Both fucosterol and saringosterol were internalized by HepG2 and CCF-STTG1 cells and activated LXRα/β, but elicited distinct metabolic effects: fucosterol increased cholesterol synthesis and intracellular desmosterol, whereas saringosterol reduced both; only saringosterol suppressed LPS-induced interleukin (IL)-6 and tumor necrosis factor (TNF)-α production in macrophages, while both enhanced cholesterol efflux. In vivo , fucosterol somewhat elevated hepatic desmosterol and decreased 5α-cholestanol and circulating oxysterols, whereas saringosterol also increased hepatic desmosterol and elevated 7α-hydroxycholesterol in liver and brain as well as serum 27-hydroxycholesterol. Transcriptome analysis revealed that fucosterol primarily modulated synaptic signaling and hormonal pathways linked to neuronal plasticity, while saringosterol affected protein quality control and neurodegenerative pathways. These data are the first on the direct comparison of the cellular and in vivo effects of fucosterol and saringosterol, revealing shared LXR activation but divergent impacts on hepatic, brain and systemic cholesterol metabolism and expression of genes involved in neural pathways, indicating complementary neuroprotective effects with therapeutic potential for AD and related disorders.

The allostatic triage model of psychopathology (ATP Model): How reallocation of brain energetic resources under stress elicits psychiatric symptoms.

CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms. A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4- arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity. The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy. Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders. The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.

Early-life stress and maternal immune activation alter stress coping behavior and brain metabolic activity in young male rats.

Inflammatory responses including glial activation, and upregulated inflammatory factors occurred after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected central nervous system. Blood-brain barrier (BBB) disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the long-lasting neurological damage even after the epidemic ends. The BBB is a highly selective dynamic interface to protects the brain from neurotoxins and the elimination of byproducts of brain metabolism via efflux transporters. The COVID-19 pandemic has introduced new challenges in managing neurological conditions, and understanding SARS-CoV-2 journey through BBB and the interconnections between the members of BBB is crucial. This review aims to summarize and elucidate the damage to the main constituent cells of BBB, including brain microvascular endothelial cells, astrocytes, and microglia and its contribution to COVID-19. Further understanding of these interactions may facilitate the development of improved treatment options and preventative measures of central nervous system injury due to COVID-19.

There is a vicious cycle between brain metabolism and epileptic seizures that compounds the deleterious consequences of seizures. Human epilepsy samples implicate cholesterol 25-hydroxylase (CH25H) in linking lipid metabolism and immunity. CH25H expression increased in microglia after status epilepticus, with its product 25-hydroxycholesterol (25-HC) accumulating in the hippocampus and blood. Thus, we generated microglia-specific CH25H knockdown mice to study the role of CH25H specifically in epilepsy. CH25H knockdown inhibited the assembly and activation of NLRP3 inflammasome and restrained the loss of neurons in the hippocampal area in epileptic mice. More importantly, CH25H knockdown reduced the number of recurrent seizures and time in seizure by electroencephalogram recording, which was partly reversed after 25-HC treatment. Untargeted metabolomics showed that another lipid metabolite, arachidonic acid, might be a potential biomarker of CH25H-mediated epilepsy. These findings suggest that microglial CH25H regulated the status epilepticus in a hydroxylase-dependent mechanism.

Enriched environment restores depressive- and anxiety-like behaviors in mice with early life stress exposure by reversing striatal function, structure and metabolism.

ObjectivePrevious studies on Alzheimer’s disease (AD) have focused on the relationships between brain pathology and gut microbiota, brain pathology and sleep, and sleep and gut microbiota, but no study has explored the relationship between these three factors. Therefore, we integrated these three factors into a unified framework and aimed to provide a reference for treating insomnia disorders (ID) in patients with AD.Patients/methodsThe 65 patients diagnosed with AD were categorized into ID group (n = 30) and non-ID group (n = 35) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep quality. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) and 18F-florbetapir (AV45)-PET scan were performed. Fecal samples were analyses using 16S rRNA amplicon sequencing. Basic data, PET, and gut microbiota were compared between the ID and non-ID groups. Finally, the relationships among the data, with differences including PSQI, were analyses. All p-values were corrected using the False Discovery Rate (FDR) method to obtain q-values.ResultsData with significant differences (p < 0.05 or q < 0.05) included PSQI, left middle frontal cortex-FDG, left Broca’s area-FDG, right thalamus (rTh)-FDG, left thalamus (lTh)-FDG, Roseburia, Prevotella 7, and Bifidobacterium. However, no differences were found between groups in AV45-PET. In the ID group, PSQI scores were significantly correlated with rTh-FDG (r = −0.612, q < 0.05), lTh-FDG (r = −0.585, q < 0.05), and Bifidobacterium (r = −0.637, q < 0.05). Partial least squares structural equation modeling revealed that Thalamic-FDG exerted a partial mediating effect in the association between Bifidobacterium and PSQI scores.ConclusionIn AD patients with ID, there may be both a direct and an indirect association between Bifidobacterium and sleep quality, with thalamic glucose metabolism mediating the indirect association, indicating that treatments aimed at enhancing brain metabolism and probiotic supplementation may improve sleep quality in this population.

Abstract Glutamate plays a central role in glioblastoma (GBM) pathophysiology, promoting tumor proliferation, excitotoxicity, and immune suppression. Emerging evidence also highlights that glioma cells integrate into normal neural circuits, and this neuronal activity drives GBM growth and progression through formation of direct glutamatergic synapses between neurons and glioma cells. Recent work by Wawro et al. (Sci Rep, 2021) demonstrated that enantiomers of 2-methylglutamate (2MeGlu), a glutamate analog, differentially modulate brain metabolism and behavior through stereoselective interactions with glutamate transport and glutamine metabolism. However, the impact of 2MeGlu on glioblastoma progression has not been studied. We employed two orthotopic mouse models of human GBM using luciferase-labeled U251 and GBM39 patient-derived xenograft cells. Approximately nine days post-implantation, mice received daily intraperitoneal injections of a racemic mixture of 2MeGlu (500 mg/kg) or vehicle control. Survival was monitored as the primary endpoint. The control and treatment groups were followed until humane endpoints were met. Tumor burden was assessed weekly using bioluminescence imaging (BLI). U251 glioma-bearing mice exhibited median survival of 26 and 35 days in the control and treatment groups, respectively (p = 0.0165). In GBM39 orthotopic xenografts, median survival of controls was 32 days. In contrast, mice treated with racemic 2MeGlu exhibited median survival of 51 days (p = 0.0004), representing a 59% increase in overall survival compared to controls. Longitudinal BLI revealed lower tumor-associated luminescence in treated animals relative to controls, consistent with reduced intracranial tumor burden. The substantial survival benefit suggests 2MeGlu may modulate glutamate-dependent metabolic or signaling pathways critical to glioblastoma growth or microenvironmental adaptation. These findings provide the first evidence that 2MeGlu confers a survival benefit in a preclinical GBM model. Given prior evidence of stereospecific effects of 2MeGlu on glutamate-glutamine cycling, future work will assess individual enantiomers for differential therapeutic efficacy and potential mechanisms of action, including altered tumor metabolism, immune microenvironment modulation, or excitotoxic stress. These studies may help establish new therapeutic vulnerabilities in glutamate-dependent glioblastoma progression.

Ferroptosis plays a key role in neuronal death and functional outcomes following traumatic brain injury (TBI). While TBI affects diverse cell types in injured brain regions, the sex- and cell type-specific responses to ferroptosis during the acute phase in the immature brain remain poorly understood. Dexmedetomidine (DEX), a selective alpha-2 adrenergic receptor agonist, has been shown to reduce inflammation and improve survival outcomes in TBI patients, but its sex- and cell type-specific effects on ferroptosis are unclear. This study investigated whether TBI induces sex- and cell type-specific ferroptotic responses and examined the effects of DEX during the acute post-injury phase in a juvenile mouse model. By concurrently isolating neurons and microglia from the same animals, we demonstrate that TBI prompts distinct sex- and cell type-specific ferroptosis responses, including differential regulation of genes involved in iron and lipid metabolism, oxidative stress, and proinflammatory pathways in neurons and microglia. DEX treatment significantly improved behavioral outcomes and reduced iron overload, lipid peroxidation, and neuroinflammation, thereby decreasing ferroptosis in both neurons and microglia. However, its effects were less prominent in neurons from female mice. Further analysis indicated that these sex- and cell type-specific responses to DEX may be partially due to differences in alpha-2 adrenergic receptor expression in neurons and microglia following TBI. Overall, our findings offer new insights into the mechanisms underlying sex- and cell type-specific responses to ferroptosis and DEX treatment, highlighting the broader implications for lipid metabolism, oxidative stress, and inflammation in the immature brain during the acute phase after TBI.Graphical Supplementary informationThe online version contains supplementary material available at 10.1007/s12035-025-05281-x.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder with two main subtypes: MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). The latest diagnostic criteria emphasize the importance of neuroimaging markers from magnetic resonance imaging (MRI) alongside clinical symptomatology assessment.This study investigates the relationship between visual MRI markers and MSA subtypes, clinical features, and cerebral glucose metabolism and striatal dopaminergic degeneration. 89 MSA patients (67 MSA-P, 22 MSA-C) underwent extensive clinical and neuropsychiatric evaluations, routine MRI scans to assess markers like the "hot cross bun" (HCB) sign, putaminal iron deposition, midbrain to pons (M/P) ratio, and cerebellar atrophy. Positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose (18F-FDG) and 11C-2β-carbomethoxy-3β(4-fluorophenyl) tropane (11C-CFT) were conducted to evaluate brain metabolism and striatal dopaminergic uptake abnormalities. Canonical Correlation Analysis revealed significant associations between clinical symptoms and MRI markers, particularly HCB sign, M/P ratio, and putaminal iron deposition. The HCB sign and M/P ratio correlated with cerebellar dysfunction, while putaminal iron deposition correlated with parkinsonism severity, particularly in MSA-P. Cerebellar and putaminal metabolism negatively correlated with their respective structural changes. However, putaminal iron deposition showed no significant correlation with striatal dopaminergic uptake. Visual MRI markers are crucial for diagnosing MSA and delineating disease subtype and symptom severity. Supratentorial and infratentorial MRI markers reflect the severity of parkinsonism and cerebellar dysfunction, respectively. Putaminal iron deposition reflects the severity of parkinsonism, suggesting that iron deposition plays an important role in the pathophysiological mechanisms contributing to parkinsonism in MSA. CCA = Canonical correlation analysis; 11C-CFT = 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane; 18F-FDG = 18Ffluorodeoxyglucose; GCIs = glial cytoplasmic inclusions; HAMA = Hamilton anxiety scale; HAMD = Hamilton depression scale; HCB = hot cross bun; H-Y = Hoehn and Yahr; MCP = middle cerebellar peduncles; MMSE = mini-mental state examination; MoCA = Montreal cognitive assessment; M/P = midbrain to pons; MSA = multiple system atrophy.

Capsaicin (CAP), the major pungent component of chili peppers, undergoes sulfation mediated by sulfotransferases (SULTs), an important phase II metabolic pathway influencing its pharmacological properties. In this study, we systematically investigated the sulfation metabolism of CAP and its underlying mechanisms in vitro and in vivo. Five sulfated metabolites were identified in rats with the liver as the primary site. Among them, M3-SO3 was the most abundant, followed by CAP-SO3 and M2-SO3, while M4-SO3 was the least abundant. SULT1C4 and SULT1E1 mainly catalyzed CAP and M2 sulfation, whereas SULT1C4 was essential for M3 sulfation. In addition, CAP sulfation occurred in multiple brain regions. Unlike the liver, brain metabolism favored M2-SO3 over M3-SO3, highlighting distinct central versus peripheral sulfation profiles. Brain microdialysis further confirmed this discrepancy. These findings provide a foundation for exploring the pharmacological roles of CAP and its sulfated metabolites, particularly within the central nervous system.

ABSTRACTDeuterium metabolic imaging (DMI) allows non‐invasive dynamic in vivo assessment of transport, uptake and metabolism of deuterated molecules. To date, DMI experiments in humans have involved ingestion of glucose‐d2 ([6,6’‐2H₂]glucose), where labelling of the sixth carbon facilitates 2H‐label transfer to pyruvate, then to lactate (Lac) via lactate dehydrogenase, or to glutamate and glutamine (Glx) via the tricarboxylic acid cycle. There are advantages to using glucose‐d7 ([1,2,3,4,5,6,6’‐2H₇]glucose) for DMI as this should yield larger signals from glucose and downstream metabolites, including deuterated water (HDO). Here, we evaluated DMI at 7 T following glucose‐d7 ingestion for monitoring glucose metabolism in the human brain. Results were compared to measurements using the same protocol but with oral glucose‐d2. Fifteen healthy volunteers participated in the study, which involved initial measurements at natural abundance, followed by 90 min of acquisition after ingestion of 0.75 g/kg glucose‐d7 (7 participants) or glucose‐d2 (8 participants). A visual stimulus was applied for 10 participants. Larger 2H signals were measured following glucose‐d7 ingestion, and whole‐brain signal ratios at times of 100 to 120 min after glucose‐d7 or glucose‐d2 ingestion for HDO, Glx and lactate (with potential contamination from lipid signals) were 1.8 ± 0.3, 1.7 ± 0.3 and 1.6 ± 0.3, respectively. At natural abundance, the SNR of the HDO signal in the CSI data was 14 ± 1. For both isotopologues, the glucose signal peaked ~80 min after ingestion, while Glx, lactate + lipid and HDO signals increased throughout the measurement period. Estimated cerebral concentrations of HDO were larger for glucose‐d7, but similar concentrations were found for glucose, Glx and lactate. No significant difference in signal or concentration between visually stimulated and unstimulated participants was found. These findings suggest that glucose‐d7 with DMI can facilitate non‐invasive in vivo assessment of metabolism in the human brain, with wide applications in experimental medicine and disease.

Prioritizing brain Metabolism: Evidence from brain temperatures of severe underweight individuals.

18F]FDG-PET provides insights into the liver-brain axis and confirms SUVgluc as a surrogate for MRGlu in a mouse model of liver fibrosis.

White matter hyperintensity-associated iron overload links glymphatic system dysfunction to cognitive impairment in cerebral small vessel disease.

Tanycytes: bloodhounds of the metabolic brain.

Traditional Chinese Medicine regulate mitochondrial dysfunction in cerebral ischemia-reperfusion injury.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are described as a disease continuum, given their shared clinical, genetic, and pathological characteristics. The comparisons of clinical and biomarker features within ALS and behavioral variant FTD (bvFTD) spectrum, would be of utmost importance for diagnostic and prognostic purposes. This study investigated biomarker differences between patients with ALS cognitively-normal (ALS-cn), ALS-FTD, and bvFTD. Participants, genetically screened for known ALS- and FTD-associated mutations, underwent neuropsychological assessments, CSF analysis, and brain imaging through 18-fluorodeoxyglucose PET ([18F]FDG-PET). Neuropsychological data were analyzed by calculating, for each cognitive domain, a composite score by averaging the rank-transformed z-scores of all tests measuring the same domain. [18F]FDG-PET analysis was performed using a validated voxel-based SPM method at single-subject and group-level. To evaluate the ability of the identified markers to differentiate ALS-cn, ALS-FTD, and bvFTD, machine-learning models-including support vector machine (SVM) and random forest (RF)-were applied, offering a streamlined, data-driven approach to improve diagnostic precision across this spectrum of disorders. 20 ALS-cn, 19 ALS-FTD, and 21 bvFTD patients were included. Neuropsychological composite z-scores revealed significant differences across groups, underlining worse performance in bvFTD regarding memory, visuospatial, language and executive functions. Brain [18F]FDG-PET showed a pattern of hypometabolism increasing from ALS-cn to ALS-FTD and reaching its greatest extent in bvFTD. Specifically, brain hypometabolism was mainly confined to the sensorimotor cortices and the frontobasal regions in the ALS-cn group, whereas in the ALS-FTD group it was extended to the supplementary motor area and the dorsolateral frontal cortex, and in the bvFTD group, a widespread hypometabolism further affected the frontomesial and orbitofrontal cortices. No significant differences in CSF biomarkers were observed. SVM correctly classified 83% of patients, indicating a good level of classification performance, while RF showed perfect accuracy (100%). The two models shared eight to ten most relevant features in the classification system, namely age, disease duration from symptoms onset to diagnosis, total composite z-score, superior frontal gyrus (left), middle frontal gyrus (left), middle frontal gyrus - pars orbitalis (left and right), and anterior cingulate cortex (left). Our study identified significant differences in the biomarkers according to the neurodegenerative clinical groups within the same disease spectrum. These differences were evident in neuropsychological profiles and brain hypometabolism patterns, successfully addressing the study's aim and providing valuable insights for differential diagnosis into ALS-FTD continuum heterogeneity.

ABSTRACTMenopause is linked to cognitive decline and reduced brain metabolism, while estrogen (E2) therapy has been shown to mitigate these effects. Understanding the molecular mechanisms by which ovarian hormones and E2 influence neuroprotection is essential for developing strategies to maintain brain health in women. In this study, we examined how the loss of ovarian hormones, with or without E2 treatment, affects the brain proteome and mitochondrial energy production in aged female C57BL/6J mice (36–40 weeks). The mice underwent sham or ovariectomy (OVX) surgery and were fed a high-fat diet for 10 weeks; six weeks after surgery, OVX mice received either sesame oil or E2 treatment for four weeks. Proteomic analysis of brain homogenates revealed 4,992 proteins regulated by E2, with pathway analysis showing increased signaling proteins related to synaptogenesis. OVX reduced proteins involved in synaptic function, branched-chain amino acid and ketone metabolism, the TCA cycle, and oxidative phosphorylation (Complexes I, IV, and V), while E2 restored protein expression within these pathways. Despite alterations in OxPhos proteins, basal and state 3 mitochondrial respiration remained unchanged, although notable impairments to Complex IV enzymatic activity were apparent in OVX, but not following E2 replacement. Overall, these results indicate that E2 supports brain health by maintaining proteins crucial for synaptic integrity and metabolism, and by reducing the decline in mitochondrial bioenergetics associated with menopause.