ACS Chemical Neuroscience最新文献

{"title":"Decoding the Nectin Interactome: Implications for Brain Development, Plasticity, and Neurological Disorders.","authors":"Shreyash Santosh Yadav, Krishnamoorthy Srinivasan, Shyam Sunder Sharma, Ashok Kumar Datusalia","doi":"10.1021/acschemneuro.5c00069","DOIUrl":"10.1021/acschemneuro.5c00069","url":null,"abstract":"<p><p>The nectin family of cell adhesion molecules (CAMs) comprising nectins and nectin-like molecules has emerged as a key regulator of various pivotal neural processes, including neuronal development, migration, synapse formation, and plasticity. Nectins engage in homophilic and heterophilic interactions to mediate cell-cell adhesion, contributing to the establishment and maintenance of neural circuits. Their extracellular domains facilitate trans-synaptic interactions, while intracellular domains participate in signaling cascades influencing cytoskeletal dynamics and synaptic function. The exhibition of distinct localization patterns in neurons, astrocytes, and the blood-brain barrier underscores their diverse roles in the brain. The dysregulation of nectins has been implicated in several neurological disorders, such as neurodevelopmental disorders, depression, schizophrenia, and Alzheimer's disease. This review examines the structural and functional characteristics of nectins and their distribution and molecular mechanisms governing neural connectivity and cognition. It further discusses experimental studies unraveling nectin-mediated pathophysiology and potential therapeutic interventions targeting nectin-related pathways. Collectively, this comprehensive analysis highlights the significance of nectins in brain development, function, and disorders, paving the way for future research directions and clinical implications.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1000-1020"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescent Sensor for the Visualization of Amino Acid Neurotransmitters in Neurons Based on an S_NAr Reaction.","authors":"Ming Xu, Peeyush Yadav, Xin Liu, Kevin D Gillis, Timothy E Glass","doi":"10.1021/acschemneuro.5c00107","DOIUrl":"10.1021/acschemneuro.5c00107","url":null,"abstract":"<p><p>Glutamate is an important excitatory neurotransmitter, while GABA is an inhibitory neurotransmitter. However, direct and accurate visualization of these important signaling agents by a chemical sensor is still very challenging. Here, a novel coumarin-based fluorescent sensor for the selective labeling and imaging of amino acids in neurons has been developed. This sensor system provides two binding sites for amino acids: an aldehyde group for the amine binding and a modified fluorobenzene for an unusual nucleophilic aromatic substitution (S_NAr) reaction of a carboxyl group. Spectroscopic studies reveal a large fluorescence enhancement upon reaction with glutamate. Compounds lacking both groups did not activate the sensor. A clear and efficient visualization of neurotransmitters in cultured hippocampus neurons was obtained by imaging studies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1238-1242"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Potential of Indole-3-acetic Acid Arylhydrazone Hybrids for Parkinson's Disease Treatment: A Comprehensive Evaluation of Neuroprotective, MAOB Inhibitory, and Antioxidant Properties.","authors":"Neda Anastassova, Magdalena Kondeva-Burdina, Nadya Hristova-Avakumova, Denitsa Stefanova, Miroslav Rangelov, Nadezhda Todorova, Denitsa Yancheva","doi":"10.1021/acschemneuro.4c00838","DOIUrl":"10.1021/acschemneuro.4c00838","url":null,"abstract":"<p><p>In the current study, a small series of five indole-3-acetic acid-derived arylhydrazone hybrids were synthesized and subjected to comprehensive evaluation of their neuropharmacological and radical-scavenging properties. Minimal neurotoxic effects were observed across diverse subcellular fractions, with particular emphasis on the compound <b>3a</b> bearing a 2,3-dihydroxy moiety, exhibiting superior neuroprotective effects against H₂O₂-induced oxidative stress by preserving the cell viability up to 68%. Noteworthy neuroprotection was observed in 6-OHDA-induced neurotoxicity using isolated rat brain synaptosomes, with compounds <b>3b</b> and <b>3c</b> displaying prominent effects. Compound <b>3a</b> demonstrated robust neuroprotective and antioxidant effects in models of <i>tert</i>-butyl hydroperoxide-induced oxidative stress on isolated rat brain mitochondria and nonenzyme-induced lipid peroxidation using isolated rat brain microsomes (Fe/AA). All compounds exhibited MAOB inhibition within the range of 0.130-0.493 μM, with compounds <b>3d</b>, <b>3e</b>, and <b>3a</b> showing notable selectivity against hMAOB. Molecular docking studies further validated ligand binding within MAOB active sites. The derivatives demonstrated scavenging activity and antioxidant effects against various ROS types, with compound <b>3a</b> consistently exhibiting the most potent activity. Structural modifications exerted discernible effects on scavenging capabilities and antioxidant effects, underscoring their potential therapeutic implications in neuroprotection and oxidative stress mitigation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1161-1181"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Donor–Acceptor Architecture-Based Potential Theranostic Fluorescent Probes for Alzheimer’s Disease","authors":"Nilesh Gajanan Bajad,&nbsp;Gajendra T. A,&nbsp;Khushboo Sharma,&nbsp;Madhu G. Tapadia,&nbsp;Ashok Kumar,&nbsp;Sairam Krishnamurthy and Sushil Kumar Singh*,&nbsp;","doi":"10.1021/acschemneuro.5c0009210.1021/acschemneuro.5c00092","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00092https://doi.org/10.1021/acschemneuro.5c00092","url":null,"abstract":"<p >The cholinergic deficits and deposition of β-amyloid (Aβ) species are regarded as the key events contributing to the progression of Alzheimer’s disease (AD). Herein, a series of novel donor–acceptor architecture-type potential theranostic agents were designed, synthesized, and evaluated for their potential against cholinesterase (ChE) enzymes and detection of Aβ species, which are primary targets in the development of therapeutics for AD. The optimal compound/probe <b>18</b> containing a benzothiazolium fluorophore with a bifunctional electron-donating <i>N</i>-aryl piperazine scaffold exhibited potent inhibitory activities against acetylcholinesterase (AChE; IC₅₀ = 0.172 ± 0.011 μM) and butyrylcholinesterase (BuChE; IC₅₀ = 1.376 ± 0.141 μM). Measurement of fluorescence properties showed that probe <b>18</b> exhibited emission maxima (λ_em) of &gt;610 nm in dimethyl sulfoxide (DMSO) and &gt;590 nm in PBS, suitable for the fluorescence imaging. <i>In vitro</i> studies demonstrated a change in fluorescence characteristics and high binding affinities (<b>18</b>; <i>K</i>_d = 0.731 μM) upon binding with Aβ aggregates. The affinity of probe <b>18</b> toward Aβ aggregates was further observed in <i>elavGAL4 &gt; UAS Aβ</i>, the <i>Drosophila</i> larval brain sections, using a fluorescence imaging technique. The <i>in vivo</i> acute oral toxicity evaluation indicated a safety profile of the lead probe 18. Moreover, <i>in vivo</i> behavioral studies including Y-maze and novel object recognition tests signified that the administration of compound <b>18</b> improved cognitive and spatial memory impairment at a dose of 10 and 20 mg/kg in the scopolamine-induced cognitive deficit model.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 7","pages":"1388–1401 1388–1401"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oroxylin A Attenuates Homocysteine-Induced Blood-Brain Barrier (BBB) Dysfunction by Reducing Endothelial Permeability and Activating the CREB/Claudin-5 Signaling Pathway.","authors":"Yilu Bao, Baiyang Sheng, Ping Lv","doi":"10.1021/acschemneuro.4c00749","DOIUrl":"10.1021/acschemneuro.4c00749","url":null,"abstract":"<p><p>Recent reports have indicated that elevated levels of homocysteine (Hcy) are closely linked to blood-brain barrier (BBB) dysfunction in neurological disorders. Oroxylin A (OA) is a key bioactive flavonoid that has been reported to regulate brain functions. However, the role of OA in Hcy-related BBB dysfunction is less reported. In this study, we aimed to elucidate the role and molecular mechanism of OA in Hcy-mediated BBB dysfunction using both <i>in vivo</i> and <i>in vitro</i> investigations. Our findings indicate that the expression of the tight junction (TJ) protein Claudin-5 declined, and the diffusion of sodium fluorescein elevated in brains of Hcy-challenged mice. These effects were notably rescued by administration of OA. In Hcy-challenged bEnd.3 brain microvascular endothelial cells, increased endothelial permeability, reduced trans-endothelial electrical resistance (TEER), and downregulated Claudin-5 were observed. These effects were significantly reversed by 25 and 50 μM OA. Interestingly, OA treatment restored the dephosphorylation of CREB at Ser133 induced by Hcy. However, the addition of the protein kinase A/cAMP-response element binding protein (PKA/CREB) inhibitor H89 counteracted the protective effects of OA on inhibiting endothelial permeability and promoting Claudin-5 expression. Together, we demonstrate that OA protects against Hcy-induced BBB dysfunction by maintaining the integrity of endothelial barriers. This protective effect is achieved through the activation of the CREB/Claudin-5 signaling pathway, highlighting the potential therapeutic value of OA in addressing BBB-related neurological disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1079-1085"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of New Pentapeptide Inhibitors Against Amyloid-β Aggregation Using Word2Vec and Molecular Simulation.","authors":"Yin-Lei Han, Huan-Huan Yin, Chen Li, Jiangyue Du, Yi He, Yi-Xin Guan","doi":"10.1021/acschemneuro.4c00661","DOIUrl":"10.1021/acschemneuro.4c00661","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides into toxic oligomers and fibrils. The efficacy of existing peptide inhibitors based on the central hydrophobic core (CHC) sequence of Aβ42 remains limited due to self-aggregation or poor inhibition. This study aimed to identify novel pentapeptide inhibitors with high similarity and low binding energy to the CHC region LVFFA using a new computational screening workflow based on Word2Vec and molecular simulation. The antimicrobial peptides and human brain protein sequences were used for training the Word2Vec model. After tuning the parameters of the Word2Vec model, 1017 pentapeptides with high similarity to LVFFA were identified. Molecular docking was employed to estimate the affinity of the pentapeptides for the target of Aβ14-42 pentamer, and 103 peptides with favorable docking scores were obtained. Finally, five pentapeptides with a low binding energy and high binding stability via molecular dynamics simulation were experimentally validated using thioflavin T assays. Surprisingly, one pentapeptide, i.e., PALIR, exhibited significant inhibition surpassing the positive control LPFFN. This study demonstrates an effective combinatorial strategy to discover new peptide inhibitors. With PALIR representing a promising lead candidate, further optimization of PALIR could aid in the development of improved therapies to prevent amyloid toxicity in AD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1055-1065"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Use of Natural Volatile Compounds on the Fibrillation Domain of Amyloid Beta (GSNKGAIIGLM)─Towards Promising Agents to Combat Alzheimer's Disease.","authors":"Zahra Dindar, Afrooz Anbaraki, Seyyed Sina Hosseini, Zohreh Harati, Aida Bahrami, Saeed Balalaie, Maryam Ghobeh, Majid Mahdavi, Arefeh Seyedarabi","doi":"10.1021/acschemneuro.4c00768","DOIUrl":"10.1021/acschemneuro.4c00768","url":null,"abstract":"<p><p>Alzheimer's disease (AD), which is caused by the accumulation of amyloid-beta, is a major medical concern today. Controlling these aggregates is critical to drug development, but delivering them effectively into the bloodstream poses significant challenges. In this context, aromatherapy has been proposed as an innovative and promising approach for AD disease. The volatile compounds cinnamaldehyde, phenylethyl alcohol, α-asarone, and β-caryophyllene have neuroprotective effects that can be effective in the treatment of neurodegenerative diseases like AD. The amyloid-beta (Aβ) fragment (25-35), which retains the properties of the full-length Aβ is used as a suitable model to evaluate the potential toxicity associated with AD. This study investigated the effects of the four mentioned volatile compounds at four different concentrations on the fibrillation process of the Aβ (25-35) peptide. Structural changes in the peptide have been analyzed using various techniques such as fluorescence probing, far-UV circular dichroism spectroscopy (CD), and atomic force microscopy (AFM). Fluorescence probing results showed that these compounds can effectively prevent the formation of amyloid fibrils by forming chemical bonds with the intermediate species. CD spectroscopy results indicated a decrease in β-sheet content of fibrils and confirmed the effect of pH on structural changes. AFM analysis revealed that volatile compounds effectively prevented the formation of amyloid fibrils at different concentrations and changed the average size of intermediates and oligomeric species. These findings show a promising future for AD patients and emphasize the importance of natural compounds in the treatment and prevention of neurodegenerative diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"1086-1102"},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143583758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Neurochemical Signature of Cardiac Arrest: A Multianalyte Online Microdialysis Study","authors":"C. Cicatiello,&nbsp;S. A. N. Gowers,&nbsp;G. K. Smith,&nbsp;D. Pinggera,&nbsp;S. Orlob,&nbsp;B. Wallner,&nbsp;A. Schiefecker,&nbsp;N. Moser,&nbsp;P. Georgiou,&nbsp;R. Helbok,&nbsp;J. Martini,&nbsp;G. Putzer and M. G. Boutelle*,&nbsp;","doi":"10.1021/acschemneuro.4c0077710.1021/acschemneuro.4c00777","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00777https://doi.org/10.1021/acschemneuro.4c00777","url":null,"abstract":"<p >This work describes the use of high resolution online microdialysis coupled with a wireless microfluidic electrochemical sensing platform for continuous monitoring of the effect of cardiac arrest and resuscitation methods on brain glucose and other key neurochemicals in a porcine model. The integrated portable device incorporates low-volume three-dimensional (3D) printed microfluidic flow cells containing enzyme-based biosensors for glucose, lactate and glutamate measurement and a complementary metal-oxide semiconductor (CMOS)-based ion-sensitive field effect transistor (ISFET) for potassium measurement. Both analysis systems incorporate wireless electronics forming a complete compact system that is ideal for use in a crowded clinical environment. Using this integrated system we were able to build a signature of the neurochemical impact of cardiac arrest and resuscitation. Our results demonstrate the almost complete depletion of brain glucose following cardiac arrest and the subsequent increase in lactate, highlighting the vulnerability of the brain while the blood flow is compromised. Following a return of spontaneous circulation, glucose levels increased again and remained higher than baseline levels. These trends were correlated with simultaneous blood measurements to provide further explanation of the metabolic changes occurring in the brain. In addition, the onset of cardiac arrest corresponded to a transient increase in potassium. In most cases glutamate levels remained unchanged after cardiac arrest, while in some cases a transient increase was detected. We were also able to validate the trends seen using online microdialysis with traditional discontinuous methods; the two methods showed good agreement although online microdialysis was able to capture dynamic changes that were not seen in the discontinuous data.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 7","pages":"1323–1334 1323–1334"},"PeriodicalIF":4.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00777","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Snake Venom-Inspired Novel Peptides Protect Caenorhabditis elegans against Paraquat-Induced Parkinson’s Pathology","authors":"Dev Madhubala,&nbsp;Rosy Mahato,&nbsp;Kangkon Saikia,&nbsp;Aparup Patra,&nbsp;Pedro Alexandrino Fernandes,&nbsp;Arun Kumar,&nbsp;Mojibur R. Khan and Ashis K. Mukherjee*,&nbsp;","doi":"10.1021/acschemneuro.4c0057610.1021/acschemneuro.4c00576","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00576https://doi.org/10.1021/acschemneuro.4c00576","url":null,"abstract":"<p >The <i>in vivo</i> protective mechanisms of two low-molecular-mass (∼1.4 kDa) novel custom peptides (CPs) against paraquat-induced neurodegenerative dysfunction in the <i>Caenorhabditis elegans</i> model were deciphered. CPs prevented the paraquat from binding to the nerve ring adjacent to the pharynx in <i>C. elegans</i> (wild-type) by stable and high-affinity binding to the tyrosine-protein kinase receptor CAM-1, resulting in significant inhibition of paraquat-induced toxicity by reducing the production of reactive oxygen species, mitochondrial membrane depolarization, and chemosensory dysfunction. The CPs inhibited paraquat-induced dopaminergic neuron degeneration and alpha-synuclein protein expression, the hallmarks of Parkinson’s disease, in transgenic BZ555 and NL5901 strains of <i>C. elegans</i>. Transcriptomic, functional proteomics, and quantitative reverse transcription-polymerase chain reaction analyses show that CPs prevented the increased expression of the genes involved in the skn-1 downstream pathway, thereby restoring paraquat-mediated oxidative stress, apoptosis, and neuronal damage in <i>C. elegans</i>. The ability of CPs to repair paraquat-induced damage was demonstrated by a network of gene expression profiles, illustrating the molecular relationships between the regulatory proteins.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 7","pages":"1275–1296 1275–1296"},"PeriodicalIF":4.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring Human Brain Metabolism via Genome-Scale Metabolic Modeling with Highlights on Multiple Sclerosis","authors":"Mustafa Sertbas,&nbsp; and ,&nbsp;Kutlu O. Ulgen*,&nbsp;","doi":"10.1021/acschemneuro.5c0000610.1021/acschemneuro.5c00006","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00006https://doi.org/10.1021/acschemneuro.5c00006","url":null,"abstract":"<p >Cerebral dysfunctions give rise to a wide range of neurological diseases due to the structural and functional complexity of the human brain stemming from the interactive cellular metabolism of its specific cells, including neurons and glial cells. In parallel with advances in isolation and measurement technologies, genome-scale metabolic models (GEMs) have become a powerful tool in the studies of systems biology to provide critical insights into the understanding of sophisticated eukaryotic systems. In this study, brain cell-specific GEMs were reconstructed for neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells by integrating single-cell RNA-seq data and global Human1 via a task-driven integrative network inference for tissues (tINIT) algorithm. Then, intercellular reactions among neurons, astrocytes, microglia, and oligodendrocytes were added to generate a combined brain model, iHumanBrain2690. This brain network was used in the prediction of metabolic alterations in glucose, ketone bodies, oxygen change, and reporter metabolites. Glucose supplementation increased the subsystems’ activities in glycolysis, and ketone bodies elevated those in the TCA cycle and oxidative phosphorylation. Reporter metabolite analysis identified L-carnitine and arachidonate as the top reporter metabolites in gray and white matter microglia in multiple sclerosis (MS), respectively. Carbamoyl-phosphate was found to be the top reporter metabolite in primary progressive MS. Taken together, single and integrated iHumanBrain2690 metabolic networks help us elucidate complex metabolism in brain physiology and homeostasis in health and disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 7","pages":"1346–1360 1346–1360"},"PeriodicalIF":4.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.5c00006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}