Metabolic brain disease最新文献

{"title":"Butyrate: a key mediator of gut-brain communication in Alzheimer's disease.","authors":"Faeze Kachoueiyan, Niosha Yahyavi Kalkhoran, Anousha Yahyavi Kalkhoran, Ashishkumar Kyada, M M Rekha, Kamlesh Chaudhary, Amit Barwal, Fadhil Faez Sead, Kamal Kant Joshi","doi":"10.1007/s11011-025-01617-7","DOIUrl":"10.1007/s11011-025-01617-7","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a prevalent neurodegenerative disorder, represents a significant global health challenge, characterized by cognitive decline and neuroinflammation. Recent investigations have highlighted the critical role of the gut-brain axis in the pathogenesis of AD, particularly focusing on the influence of short-chain fatty acids (SCFAs), metabolites produced by the gut microbiota through the fermentation of dietary fiber. Among SCFAs, butyrate has emerged as a crucial mediator, positively impacting various pathological processes associated with AD, including epigenetic regulation, neuroinflammation modulation, maintenance of the blood-brain barrier (BBB), enhanced intestinal integrity, regulation of brain metabolism, and interference with amyloid protein formation as well as tau protein hyperphosphorylation. Furthermore, distinctions in butyrate profile and microbial communities have been observed between AD patients and healthy individuals, underscoring the importance of gut microbiota in AD progression. This review summarizes the current understanding of the many functions of butyrate in reducing the consequences of AD and emphasizes the possibility of addressing the gut microbiota as a therapeutic approach to managing AD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"189"},"PeriodicalIF":3.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033375","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":"Neuroprotective potential of hispidulin and diosmin: a review of molecular mechanisms.","authors":"Anish Singh, Lovedeep Singh, Diksha Dalal","doi":"10.1007/s11011-025-01615-9","DOIUrl":"10.1007/s11011-025-01615-9","url":null,"abstract":"<p><p>Flavonoids are an important class of natural products, particularly, belong to a class of plant secondary metabolites having a polyphenolic structure. They are widely found in fruits, vegetables, and certain beverages. Hispidulin and diosmin are naturally occurring flavonoids recognized for their potential health benefits, such as antioxidant, anti-inflammatory, and neuroprotective properties. Hispidulin is present in several plants, including Arnica montana, Salvia officinalis (sage), and Eupatorium arnottianum. Diosmin is mainly extracted from citrus fruits like lemons and oranges and can also be synthesized from hesperidin, another flavonoid found in citrus fruits. Neurodegenerative diseases are characterized by complex signaling pathways that contribute to neuronal deterioration. The JAK/STAT pathway is involved in inflammatory responses, while the NF-κB/NLRP3 pathway is associated with metabolic stress and inflammation, both facilitating neurodegeneration. Conversely, the AMPK/pGSK3β pathway is crucial for neuroprotection, regulating cellular responses to oxidative stress and promoting neuronal survival. Additionally, the BACE/Aβ pathway exacerbates neuronal damage by triggering inflammatory and oxidative stress responses, highlighting critical targets for therapeutic strategies. Hispidulin and diosmin have emerged as promising agents in the modulation of mediators involved in neuroinflammation and neurodegenerative diseases. Oxidative stress and inflammatory pathways, including those driven by Aβ/BACE1 and JAK/STAT signaling, are central to neuronal damage and disease progression. Recent studies highlight that hispidulin and diosmin exhibit notable neuroprotective effects by targeting these mediators. Hispidulin has been shown to impact key inflammatory cytokines and adhesion molecules, while diosmin influences proinflammatory cytokine production and inflammasome activation. Both compounds offer potential therapeutic benefits by modulating crucial mediators linked to neuroinflammation and neurodegeneration. This review article is designed to explore the intricate mechanistic interplay underlying the neuroprotective effects of hispidulin and diosmin.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"188"},"PeriodicalIF":3.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018335","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":"Rumex acetosa L. enhance learning and cognitive function by modulating NMDA receptor and BDNF pathways in vitro and in vivo.","authors":"Dool-Ri Oh, Yujin Kim, Bo Yeong Mun, Haeju Ko, Yonguk Kim, Moon Jong Kim, Kyo-Nyeo Oh, Ji-Ae Hong, Donghyuck Bae","doi":"10.1007/s11011-025-01608-8","DOIUrl":"10.1007/s11011-025-01608-8","url":null,"abstract":"<p><p>Rumex acetosa L. (RA), a member of the Polygonaceae family, is called sorrel and has been used as a vegetable and traditional medicine. RA has various bioactive functions; however, its effects on cognitive function remain unclear. Herein, we investigated the learning- and memory-enhancing effects of RA in rats using the Morris Water Maze (MWM) test. In addition, we evaluated the effect of RA on cognitive function in the hippocampus, both in vitro and in vivo, to identify the underlying molecular mechanisms. RA showed cognitive enhancing effects by activating cyclic AMP-responsive element-binding protein (CREB) via N-methyl-d-aspartate (NMDA) receptor 2 subunits (NR2A and NR2B), postsynaptic density protein-95 (PSD-95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit (GluA1) signaling in primary cultured rat hippocampal neurons. For the in vivo experiments, RA was orally administered to SD rats for 26 days. RA showed significantly decreased escape latency on the first (acquisition) and last (retention) trials on the 2nd and 3rd training days and increased entry into the platform quadrant of time and distance on the probe trial. Furthermore, RA significantly increased NR2A, NR2B, PSD-95, and GluA1 the following downstream signaling extracellular signal-regulated kinase 1/2 (ERK1/2), calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, and brain-derived neurotrophic factor (BDNF) in the hippocampus. These results demonstrate that RA improves cognitive function, including synaptic plasticity, by regulating the NMDA receptor-dependent and BDNF/CREB signaling pathways.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"185"},"PeriodicalIF":3.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972296","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":"High urea promotes mitochondrial fission and functional impairments in astrocytes inducing anxiety-like behavior in chronic kidney disease mice.","authors":"Xi Zhao, Shengyao Zhang, Mengna Wu, Binyun Zhang, Guoran Wan, Meng Zhang, Jing Li, Zhuo Fei, Guoqi Zhu, Shaoqiu Jiang, Mohan Xiao, Wanjia Liu, Zhelun Zhao, Boyue Huang, Jianhua Ran","doi":"10.1007/s11011-025-01612-y","DOIUrl":"10.1007/s11011-025-01612-y","url":null,"abstract":"<p><p>High urea can induce depression and anxiety. Activation of astrocytes is closely associated with psychiatric disorders. However, the pathological mechanism of whether high urea affects astrocyte structure and function to induce anxiety-like behaviors remain unclear. We established a high-urea chronic kidney disease (CKD) mouse model and found that these mice exhibited elevated levels of anxiety through behavioral experiments. Immunofluorescence and transmission electron microscopy studies of astrocytes revealed a decrease in density and branching of mPFC astrocytes. Additionally, we observed a significant reduction in ATP and BDNF levels in the mPFC and primary astrocytes of CKD mice induced by high urea. Analysis of gene expression differences in astrocytes between WT and high-urea mice indicated alterations in mitochondrial dynamics-related signaling pathways in astrocytes. We established a high-urea primary astrocyte model to assess mitochondrial function and levels of fusion and fission proteins. Treatment of primary astrocytes with high urea led to mitochondrial fragmentation and downregulation of Mfn2 expression. These results suggested that high urea downregulates Mfn2 expression in mPFC astrocytes, induced mitochondrial fusion-fission abnormalities, disrupted astrocyte energy metabolism, and promoted high-urea-related anxiety. Mfn2 may represent a potential therapeutic target for high-urea-related anxiety.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"186"},"PeriodicalIF":3.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144033546","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":"Oxymatrine impedes Alzheimer's progression via the attenuation of hypercholesterolemia and fibrosis.","authors":"Ashmita Das, Rahul Manna, Durlav Chowdhury, Dilip Sharma, Surendra H Bodakhe","doi":"10.1007/s11011-025-01606-w","DOIUrl":"10.1007/s11011-025-01606-w","url":null,"abstract":"<p><p>This study highlights the potential therapeutic benefits of oxymatrine (OMT), a quinolizidine alkaloid found in Sophora flavescens, for Alzheimer's disease (AD). This study connects the dots between metabolic and neuronal origins by exploring the effects of oxymatrine in slowing down hypercholesterolemic and fibrotic changes that contribute to cognitive deficits. In our study, laboratory rats were fed a high-cholesterol diet for eight weeks. Cognitive abilities were assessed weekly using Hebb's Williams Maze and Radial arm mazes. Additionally, intraperitoneal doses of OMT were administered (20 mg/kg, 40 mg/kg, and 80 mg/kg) for 21 days. Furthermore, using ELISA, plasma and brain oxysterols, transforming growth factor β, amyloid β, matrix metalloproteinase- 9, claudin- 5, and ATP Binding Cassette Transporter A1 levels were measured biweekly. High-density lipoprotein, low-density lipoprotein, aspartate aminotransferase, and alanine transaminase levels were estimated using diagnostic kits. The findings demonstrate that The administration of oxymatrine to experimental animals resulted in a dose-dependent synergistic decline in several biomarkers, including oxysterols, transforming growth factor β, amyloid β, matrix metalloproteinase- 9, low-density lipoprotein, aspartate aminotransferase, and alanine transaminase levels. At the same time, a concomitant increase in the levels of Claudin- 5, ATP Binding Cassette transporter A1, high-density lipoprotein, and antioxidants in the same animals was observed, especially at a dose of 80 mg/kg. This study aims to establish a link between metabolic and neural origins by investigating the effects of oxymatrine in reducing the progression of hypercholesterolemia and fibrosis, which contribute to cognitive impairment in AD. The research explores how oxymatrine regulates mediators involved in oxysterol production and fibrotic alterations in AD. Preliminary results suggest that oxymatrine has the potential to significantly delay the development and progression of AD, offering a promising treatment alternative for those affected by the disease. The findings of the present study strongly suggest that OMT effectively retards the progression of AD, which is commonly associated with the intake of high-cholesterol diets. Subsequent investigations ought to examine the molecular mechanisms behind oxymatrine's interaction with oxysterols and lipid metabolism, including sophisticated imaging methodologies and metabolomics. Longitudinal studies are essential to evaluate the long-term efficacy and safety of oxymatrine in both animal models and people. Exploring its possible synergistic effects with current medications may yield more effective therapeutic techniques. Identifying biomarkers for personalised medication may also be beneficial. Clinical trials and research on oxymatrine's potential as a prophylactic medication may yield significant insights.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 5","pages":"187"},"PeriodicalIF":3.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971875","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":"Hepatic encephalopathy as an indication or contraindication to liver transplant?","authors":"Mette Munk Lauridsen, Jasmohan S Bajaj","doi":"10.1007/s11011-025-01614-w","DOIUrl":"https://doi.org/10.1007/s11011-025-01614-w","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) presents a significant challenge in liver transplantation (LT). On the one hand, LT can provide a curative treatment for HE by addressing its underlying cause, suggesting HE should be a strong indication for LT. Conversely, the severity of HE may reflect advanced liver disease and significant neurocognitive impairment, potentially complicating post-transplant outcomes and raising concerns about its suitability as an indication. This review will provide helpful insight to the hepatologist deciding whether HE should be considered an indication or a contraindication to liver transplantation in their patient. It gives an overview of the burden of HE pretransplant, HE's current status in the transplant listing process, and pre- and post-transplant cognitive issues to be mindful of. The main take-away messages are that pre-transplant HE should be managed aggressively, that neurodegenerative disorders and other differential diagnoses to HE should be thoroughly excluded, and that immunosuppressants can cause new onset cognitive issues post-transplant and should be monitored closely. In the future, objective measures of HE severity should be included in the MELD score to enhance the fairness and efficacy of transplant listings, ensuring those with cirrhosis complicated by HE receive timely and appropriate treatment.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"181"},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018406","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":"The role of Panax ginseng in neurodegenerative disorders: mechanisms, benefits, and future directions.","authors":"Faranak Mehrnoosh, Dorsa Rezaei, Seyed Abbas Pakmehr, Paria Ganji Nataj, Mustafa Sattar, Melina Shadi, Payam Ali-Khiavi, Farshad Zare, Ahmed Hjazi, Raed Fanoukh Aboqader Al-Aouadi, Valisher Sapayev, Faranak Zargari, Ali G Alkhathami, Roya Ahmadzadeh, Mohammad Khedmatgozar, Sina Hamzehzadeh","doi":"10.1007/s11011-025-01610-0","DOIUrl":"https://doi.org/10.1007/s11011-025-01610-0","url":null,"abstract":"<p><p>Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Multiple sclerosis (MS), and Huntington's disease (HD) represent a growing global health challenge, especially with aging populations. Characterized by progressive neuronal loss, these diseases lead to cognitive, motor, and behavioral impairments, significantly impacting patients' quality of life. Current therapies largely address symptoms without halting disease progression, underscoring the need for innovative, disease-modifying treatments. Ginseng, a traditional herbal medicine with well-known adaptogenic and neuroprotective properties, has gained attention as a potential therapeutic agent for neurodegeneration. Rich in bioactive compounds called ginsenosides, ginseng exhibits antioxidant, anti-inflammatory, and anti-apoptotic effects, making it a promising candidate for addressing the complex pathology of neurodegenerative diseases. Recent studies demonstrate that ginsenosides modulate disease-related processes such as oxidative stress, protein aggregation, mitochondrial dysfunction, and inflammation. In AD models, ginsenosides have been shown to reduce amyloid-beta accumulation and tau hyperphosphorylation, while in PD, they help protect dopaminergic neurons and mitigate motor symptoms. Ginseng's effects in ALS, MS, and HD models include improving motor function, extending neuronal survival, and reducing cellular toxicity. This review provides a comprehensive overview of the neuroprotective mechanisms of ginseng, emphasizing its therapeutic potential across various neurodegenerative diseases and discussing future research directions for its integration into clinical practice.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"183"},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001913","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":"Intermittent fasting reduces interictal epileptiform discharges and hippocampal reactive astrogliosis during electrical kindling epileptogenesis.","authors":"Josué Denichi Sánchez-Hernández, Joaquín Manjarrez-Marmolejo, Octavio Fabián Mercado-Gómez, Angélica Vega-García, Javier Franco-Pérez, Virginia Selene Arriaga-Ávila, Sandra Orozco-Suárez, Rosalinda Guevara-Guzmán","doi":"10.1007/s11011-025-01607-9","DOIUrl":"https://doi.org/10.1007/s11011-025-01607-9","url":null,"abstract":"<p><p>It has been proposed that interictal epileptiform discharges observed in epilepsy-related structures, such as the hippocampus contributes to epileptogenesis. Intermittent fasting (IF) produces anticonvulsant effects protecting against experimentally induced seizures. It has been suggested that protective effects could be associated with astrocytic metabolic changes. However, it is unknown whether IF modifies the epileptogenic process. Therefore, this work aimed to analyze the impact of IF on interictal epileptiform discharges in the rat hippocampus and their possible correlation with astrocytic activation. Male Wistar rats were divided into two groups: one group had free access to food, while the other group was subjected to IF (food was provided for 2 h a day). Both groups underwent a hippocampal electrical kindling protocol with 36 stimulations. Our results showed that IF inhibited the incidence of generalized seizures induced by kindling and significantly reduced the total spectral power of interictal epileptiform discharges in the hippocampus. Furthermore, IF prevented the rise in fasting blood glucose and reduced seizure-induced astrogliosis by preventing the GFAP expression and the morphological complexity of astrocytes in the hippocampal CA3 region. These results support the notion that IF modifies epileptogenesis by modulating hippocampal hyperexcitability during the interictal stage, which could be associated with reductions in glucose metabolism and astrogliosis.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"182"},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035361","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":"Targeted metabolomics in children with autism spectrum disorder with and without developmental regression.","authors":"Chakkera Priyanka, Rita Christopher, Madhu Nagappa, John Vijay Sagar Kommu, Meghana Byalalu Krishnadevaraje, Durai Murukan Gunasekaran, Binu V S Nair, Raghavendra Kenchaiah, Nandakumar Dalavalaikodihalli Nanjaiah, Mariamma Philip, Sanjay K Shivanna, Pragalath Kumar Appadorai, Hansashree Padmanabha","doi":"10.1007/s11011-025-01604-y","DOIUrl":"https://doi.org/10.1007/s11011-025-01604-y","url":null,"abstract":"<p><p>Early diagnosis and intervention in children with autism spectrum disorder (ASD) is crucial. At present, diagnosis of ASD is primarily based on subjective tools. Identifying metabolic biomarkers will aid in early diagnosis of ASD complementing the assessment tools. The study aimed to conduct targeted metabolomic analysis and determine the plasma metabolites that can discriminate children with ASD from typically developing children (TD), and to determine the utility of machine learning in classifying ASD children based on the metabotypes. This was a multi-centric, analytical, case-control study conducted between April 2021-April 2023. Fasting plasma samples were obtained from seventy ASD and fifty-eight TD children, aged 2 to 12 years. Samples were quantitively analysed for 52 targeted metabolites (13 amino acids, 37 acylcarnitines, adenosine and 2-deoxyadenosine levels) using tandem mass spectrometry. An in-depth statistical analysis was performed. A total of 26 metabolites (11 amino acids, 14 acyl carnitines and adenosine) were found to be significantly (p < 0.005) different between ASD and TD children. Adenosine and amino acid levels were significantly decreased in ASD children. Among acyl carnitines, short- and long-chain acyl carnitine levels were significantly decreased, while medium-chain acyl carnitine levels were significantly increased in ASD children. Octenoylcarnitine-C8:1 (Cut-off value- 0.025 mmol/L, AUC- 0.683) and adenosine (Cut-off value- 0.025 mmol/L, AUC- 0.673) were found to predict children with ASD at a sensitivity of 55.7% and 57.1%, specificity of 79.3% and 72.4% respectively. Based on the metabolites, machine learning models like Support Vector Machine (SVM) and Random Forest (RF) were able to discriminate ASD from TD children with the classification accuracy score being highest in RF (79.487%, AUC- 0.800). Significant abnormalities in plasma metabolites were observed leading to disturbances in the Krebs cycle, urea cycle and fatty acid oxidation, suggesting mitochondrial dysfunction that may possibly contribute in the pathobiology of ASD. Octenoylcarnitine-C8:1 and Adenosine may serve as potential metabolic biomarkers for ASD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"184"},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008282","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":"ADAMTS18 deficiency leads to abnormal brain methylation metabolism, dysregulated neuroinflammatory response, and unsound blood-brain barrier structure in mice.","authors":"Hanlin Liu, Fangmin Xu, Mengxi Zhang, Xiaohan Niu, Suying Dang, Wei Zhang","doi":"10.1007/s11011-025-01609-7","DOIUrl":"https://doi.org/10.1007/s11011-025-01609-7","url":null,"abstract":"<p><p>ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family is a group of secretory proteases involved in the maintenance of central nervous system (CNS) homeostasis and neuronal disease. ADAMTS18 is a member of this family and has been linked to the integrity of the human brain's white matter. However, the cellular and molecular basis of ADAMTS18 in brain metabolism and homeostasis remains unclear. In this study, a total of 47,719 genes were identified in 8 independent wild type (WT) and Adamts18 knockout (KO) mouse brain samples using brain transcriptomic analysis. The abundance of 100 genes in brain was significantly different between WT and KO mice. ADAMTS18 deficiency resulted in decreased S-adenosine homocysteine hydrolase (SAHH) levels, impaired brain methyl cycle metabolism and dysregulation of neuroinflammatory-related factors (e.g., Lrg1, and Lcn2) in mouse brain. The number and branching complexity of microglia in brain tissue of Adamts18 KO mice were significantly reduced. Adamts18 KO mice also showed poor blood-brain barrier (BBB) integrity. Mechanically, ADAMTS18 deficiency resulted in significant downregulation of Il- 34, Csf1r, Cx3cl1, Cx3cr1, Fn, Tgfb1, Tgfbr2, Smad4 and Sall1 genes related to microglia expansion, migration, characteristic development and maintenance. BBB integrity related markers Glut1, Plvap, Zo- 1, Occludin or Aqp- 4 were partially dysregulated in the brain tissue of Adamts18 KO mice and significantly deteriorated after LPS stimulation. Collectively, these results shed light on the significance of ADAMTS18 in brain methyl cycle metabolism, neuroinflammatory regulation and BBB structure maintenance.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"179"},"PeriodicalIF":3.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971073","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}