Metabolic brain disease最新文献

{"title":"TCE-mediated neuroprotection against rotenone-induced dopaminergic neuronal death in PD mice: insights into the Nrf-2/PINK1/Parkin-mitophagy pathway.","authors":"Hagera Dilnashin, Shekhar Singh, Poonam Rawat, Aaina Singh Rathore, Richa Singh, Priyanka Kumari Keshri, Nitesh Kumar Gupta, Singh Ankit Satyaprakash, Surya Pratap Singh","doi":"10.1007/s11011-025-01595-w","DOIUrl":"https://doi.org/10.1007/s11011-025-01595-w","url":null,"abstract":"<p><p>Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease (PD). In a previous study, we reported that an extract of T. cordifolia (TCE) possessed antioxidant and anti-apoptotic properties that improved mitochondrial function against rotenone-induced neurotoxicity. However, the underlying molecular mechanism remains unclear. In this study, we found that rotenone (ROT)-induced PD mice exhibited mitochondrial abnormalities, including defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression, and mitochondrial fragmentation, accompanied by reduced expression of Pink1 and Parkin and increased apoptosis. These changes were partially reversed following oral administration of TCE. Moreover, TCE restored the activity and translocation of NF-E2-related factor 2 (Nrf2) and upregulated the expression of antioxidant enzymes (SOD1, SOD2, GSH, and GSSH). Interestingly, ROT also activates mitophagy. Our results suggest that ROT toxicity can cause neuronal cell death through mitophagy-mediated signaling in PD mice. However, TCE reversed this activity by inhibiting autophagic protein (LC3B-II/LC3B-I) activation and increasing specific mitochondrial proteins (TOM20, Pink1, and Parkin). Our findings indicated that TCE provides neuroprotection against rotenone-induced toxicity in PD mice by stimulating endogenous antioxidant enzymes and inhibiting ROT-induced oxidative stress by potentiating the Nrf-2/Pink1/Parkin-mediated survival mechanism.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"172"},"PeriodicalIF":3.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795815","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":"Maternal-offspring brain and tissue cross-talk in preeclampsia: insights from a rat model.","authors":"Xiaomin Xu, Haiyin Chen, Lidan Gao, Congcong Sun, Xiaoqing Li, Yanjun Li, Wenhuan Wang, Yanyan Zheng","doi":"10.1007/s11011-025-01593-y","DOIUrl":"10.1007/s11011-025-01593-y","url":null,"abstract":"<p><p>This study aimed to investigate the differential metabolic profiles across maternal and offspring brains, serum, and placental tissues in preeclampsia (PE), with a particular focus on elucidating the maternal-offspring brain and tissue cross-talk that may contribute to the complex pathophysiology of PE. PE was induced in rats using the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) to simulate both early-onset PE (EOPE) and late-onset PE (LOPE). We utilized non-targeted proton nuclear magnetic resonance (NMR) metabolomics to characterize the metabolic profiles of serum, placental tissue extracts, and brain tissues from both mothers and offspring. Multivariate analysis, Spearman correlation, Density-Based Spatial Clustering of Applications with Noise algorithm, Data-Driven Statistical Predictive Correlation network analysis and Tissue heterogeneity analysis were employed to explore tissue-specific metabolic signatures and their interactions. Following L-NAME induction, both EOPE and LOPE presented significant metabolic differences and shared traits across tissues, with distinct tissue-specific responses characterizing the metabolic profile of PE. Serum from both PE groups showed a decrease in tryptophan, isobutyrate, and lactate, with an increase in betaine. Lactate was upregulated in placental tissues, highlighting its metabolic role. Extensive intra-tissue metabolic correlations and inter-tissue metabolite exchanges were detected among the maternal brain, serum, placenta, and offspring brain across all three experimental groups. EOPE and LOPE exhibited distinctly different metabolic characteristics and trajectories of differential metabolites, along with diverse interaction patterns between the maternal/offspring brain and the placenta. This study uncovers the multi-tissue metabolic remodeling in response to preeclampsia, implying that addressing pathophysiological stress is crucial and may have potential implications for neurological outcomes. The comprehensive analysis highlights the pivotal role of the brain-placenta axis in preeclampsia, advocating for a classified diagnostic and management approach.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"173"},"PeriodicalIF":3.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795812","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 bioactive natural products for treating neurodegenerative diseases: a computational network medicine approach targeting the estrogen signaling pathway in amyotrophic lateral sclerosis and Parkinson's disease.","authors":"Mayank Roy Chowdhury, Ramireddy Venkata Sai Reddy, Navaneeth K Nampoothiri, Rajeswara Reddy Erva, Sudarshana Deepa Vijaykumar","doi":"10.1007/s11011-025-01585-y","DOIUrl":"https://doi.org/10.1007/s11011-025-01585-y","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share overlapping molecular mechanisms, including estrogen signaling dysregulation, oxidative stress, and neuroinflammation. Standard treatments often lead to adverse effects due to unintended cross-talk with the estrogen signaling pathway. Identifying key regulatory genes and bioactive plant-derived compounds that modulate estrogen signaling without interfering with standard therapies offers a promising neuroprotective strategy. A network medicine and systems biology approach was used, beginning with the screening of 29 medicinal plants for ALS and 49 for PD, identifying 12 shared plants with neuroprotective potential. Bioactive compounds were screened for gene, protein, and pathway interactions, leading to target prediction (846 ALS-related and 690 PD-related targets) and disease association mining, which identified 93 overlapping genes (OGs). Protein-protein interaction (PPI) network analysis and MCODE clustering revealed ESR1, EGFR, and SRC as key hub-bottleneck (HB) genes, further validated via differential gene expression analysis. Gene ontology (GO) and pathway enrichment analyses revealed significant enrichment in estrogen signaling confirming the involvement of HB genes in neurodegenerative disease progression. Differential expression analysis confirmed ESR1 upregulation in ALS but downregulation in PD, suggesting a converse disease-specific regulatory pattern. Gene regulatory network (GRN) analysis identified hsa-miR-145-5p (ALS) and hsa-miR-181a-5p (PD) as key regulators, while FOXC1, GATA2, and TP53 emerged as crucial transcription factors (TFs) influencing disease progression. Molecular docking and MD simulations validated strong and stable interactions of Eupalitin (CYP19A1, -9.0 kcal/mol), Hesperetin (ESR1, -8.1 kcal/mol), and Sumatrol (PIK3CA, -8.9 kcal/mol). These phytochemicals, derived from Rosmarinus officinalis, Artemisia scoparia, Ocimum tenuiflorum, and Indigofera tinctoria, maintained stable hydrogen bonding and hydrophobic interactions for over 30% of a 25 ns simulation, supporting their therapeutic potential. The identification of ESR1, EGFR, and SRC as key targets, alongside estrogen signaling involvement, highlights the need for targeted nutraceutical interventions. These findings pave the way for safer, plant-based therapies that mitigate neurodegeneration while preserving estrogen signaling integrity, offering a promising adjuvant strategy alongside existing treatments.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"169"},"PeriodicalIF":3.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780629","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":"Xifeng Jiannao pill mitigates MPTP-induced neuronal apoptosis by reducing inflammation and oxidative stress via MAPK signaling.","authors":"Xiangli Han, Guoping He, Juanjuan Wang, Hanxi Lou, Lei Chen, Lei Zhang, Boyang Liu, Di Wu, Xiaozhi Liu, Su Wang, Chunyan Zhang, Liping Guo","doi":"10.1007/s11011-025-01597-8","DOIUrl":"10.1007/s11011-025-01597-8","url":null,"abstract":"<p><p>Xifeng Jiannao Pill (XFJNP), a traditional Chinese medicine formulation, has been shown to alleviate clinical symptoms in patients with Parkinson's disease (PD). However, the underlying mechanisms remain unclear. Therefore, this study employs network pharmacology and molecular biology to investigate the potential therapeutic mechanisms of XFJNP. Firstly, network pharmacology is utilized to screen the major active ingredients and potential targets of XFJNP in the treatment of PD. Following this, pathway enrichment analysis is conducted to gain insights into the underlying mechanisms. Secondly, an MPP⁺-induced SH-SY5Y cell model and an MPTP-induced PD mouse model to investigate the therapeutic effects and potential mechanisms of XFJNP on PD. By assessing apoptosis, oxidative stress (OS), inflammation, activation of the MAPK pathway, and conducting behavioral tests in mice, we aimed to elucidate the efficacy and underlying mechanisms of XFJNP in treating PD. Network pharmacology analysis indicates that the MAPK signaling pathway holds a key position in mediating the therapeutic effects of XFJNP for PD. In basic experimental studies, XFJNP significantly enhanced the survival rate of MPP⁺-induced SH-SY5Y cells in vitro, reduced OS and inflammation levels, and increased the expression of tyrosine hydroxylase (TH) protein. In the MPTP-induced PD mouse model, XFJNP effectively improved motor function and reduced the loss of dopaminergic (DA) neurons. Mechanistic studies suggest that XFJNP may mitigate OS and inflammatory responses in the substantia nigra by inhibiting the excessive activation of ERK, JNK, and p38 in the MAPK signaling pathway. Based on the results of network pharmacology analysis and experimental validation, XFJNP displays profound neuroprotective efficacy by modulating the MAPK signaling cascade, markedly diminishing neuroinflammation and mitigating OS-triggered apoptosis of DA neurons in PD models.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"170"},"PeriodicalIF":3.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11971062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780631","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":"Alleviating effect of antioxidants on combined chromium and cadmium-induced neurotoxicity and apoptosis by activating the Nrf2-keap1 and associated pathway in Swiss albino mice.","authors":"Swapnil Tripathi, Dharati Parmar, Samir Raval, Shivkumar Prajapati, Gyanendra Singh","doi":"10.1007/s11011-025-01594-x","DOIUrl":"https://doi.org/10.1007/s11011-025-01594-x","url":null,"abstract":"<p><p>Chromium (Cr) and cadmium (Cd) are well-known cytotoxic and carcinogenic elements co-existing in the biosphere. Though their separate toxicities have been well researched, little is known about their combined effects, particularly with regard to the cellular stress response. The current study intends to explore the individual and combined toxic effects of Cr and Cd in the brain of Swiss albino mice in addition to examining the possible neuroprotective functions of coenzyme Q10 (CoQ10), biochanin-A (BCA), and phloretin (PHL), the naturally occurring flavonoids with antioxidant qualities. Mice were administered orally with Cr and Cd (75 ppm each) along with the i.p. dose of CoQ10 (10 mg/kg), BCA, and PHL (50 mg/kg each), respectively. After two weeks of treatment, an array of biochemical assays, histopathological examination, and gene expression analyses were carried out to evaluate the underlying mechanisms of the selected nutraceuticals. Our findings, which underscore the importance of this research, demonstrated that the administration of the nutraceuticals reduced oxidative stress and restored the antioxidant defense system by decreasing the levels of malondialdehyde (MDA) and protein carbonyl content (PCC) with concomitant increase in superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH), and total thiol (TT) activity. A decrease in cholinesterase activity was also observed, along with the altered histo-architecture. The qRT-PCR analysis of mRNA expression revealed the upregulation of genes associated with antioxidant defense (SIRT1, Nrf2, HO-1, NQO1) along with the downregulation of the apoptotic markers caspase-8 and 3, respectively. The study highlights the neuroprotective effects of CoQ10, BCA, and PHL against Cr and Cd-induced oxidative stress via enhancing Nrf2-mediated exogenous antioxidant defenses and mitigating cellular damage and neural apoptosis. These results imply that these nutraceuticals may have therapeutic value in alleviating neurological disorders brought on by heavy metal exposure, with potential significant impact on future treatments.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"171"},"PeriodicalIF":3.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780620","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":"Ginsenoside CK modulates glucose metabolism via PPARγ to ameliorate SCOP-induced cognitive dysfunction.","authors":"Na Li, Xingyu Fang, Hui Li, Jian Liu, Nan Chen, Xiaohui Zhao, Qing Yang, Xijun Chen","doi":"10.1007/s11011-025-01596-9","DOIUrl":"10.1007/s11011-025-01596-9","url":null,"abstract":"<p><p>Ginsenoside compound K (CK) exhibits neuroprotective properties; however, the underlying mechanisms behind these effects have not been investigated thoroughly. CK is the primary active compound derived from ginseng and is metabolized in the gut. It enhances neuronal function by modulating the gut microflora. Therefore, the present study aimed to elucidate the mechanism through which CK enhances cognitive function, employing gut microbiome and microarray analyses. The results revealed that CK upregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), suppressed amyloid-β (Aβ) aggregation in hippocampal neurons, and influenced the expression of cyclin-dependent kinase-5 (CDK5), (including insulin receptor substrate 2) IRS2, insulin-degrading enzyme (IDE), glycogen synthase kinase-3 beta (GSK-3β), glucose transporter type 1 (GLUT1), and glucose transporter type 3 (GLUT3) proteins. These proteins play crucial roles in regulating brain glucose metabolism, increasing neuronal energy, and reducing neuronal apoptosis, thereby ameliorating cognitive impairment in mice.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"168"},"PeriodicalIF":3.2,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772440","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":"Ferroptosis and Alzheimer's: unveiling new avenues for the treatment and prevention.","authors":"Veerta Sharma, Prateek Sharma, Thakur Gurjeet Singh","doi":"10.1007/s11011-025-01587-w","DOIUrl":"https://doi.org/10.1007/s11011-025-01587-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD), one of the most prevalent neurodegenerative illnesses worldwide, has a devastating effect on individual, families and society. Despite the extensive research and effort, various clinical trials aimed against amyloid-β, which is suspected to have a causative role in the illness, have not yet shown any clinically significant success to date. Emerging evidence suggests that ferroptosis, a kind of programmed cell death triggered by lipid peroxidation and dependent on iron, plays a role in AD. There is a complex relationship between AD and ferroptosis. In both the processes iron dysregulation, altered anti-oxidant mechanisms and lipid peroxidation is involved. Ferroptotic processes contributes to the neuro-inflammation, oxidative stress and damage to the neurons as observed in AD. Additionally, amyloid-β, a hallmark of AD, may influence the ferroptosis, further linked the two pathways. Numerous signalling pathways such as Phospho inositide 3-kinase, Glycogen synthase kinase-3β, 5'-AMP-activated protein kinase, nuclear factor erythroid 2-related factor-2 and Sirtuin pathway plays a part in the pathophysiology of AD. Through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (ferroptotic inhibitors) and AD-related pathways. Furthermore, this review highlights the various ferroptotic inhibitors as the therapeutic agents for the slowing down the progression of AD. The crosstalk between these processes could unveil the potential therapeutic targets for the AD treatment.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"167"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753496","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":"Ursolic acid derivatives improved clinical signs of experimental autoimmune encephalomyelitis by modulating central nervous system inflammation.","authors":"Elaine Carlos Scherrer, Karla Antunes Ramos, Ydia Mariele Valadares, Igor Gabriel Machado Soares, Alessandra Paula Carli, Fernando Sá Silva, Jeferson Gomes Silva, Daniel Gomes Alvarenga, Alessa Sin Singer Brugiolo, Rodrigo Moreira Verly, Maiara Rodrigues Salvador, Angelo Marcio Leite Denadai, Caio César Souza Alves, Sandra Bertelli Ribeiro Castro","doi":"10.1007/s11011-025-01591-0","DOIUrl":"https://doi.org/10.1007/s11011-025-01591-0","url":null,"abstract":"<p><p>The immunopathogenesis of multiple sclerosis (MS) involves the activation of T lymphocytes, leading to progressive axonal loss and brain atrophy. Ursolic acid (AU) has been widely used as an herbal medicine, with the ability to inhibit the production and secretion of cytokines and may influence the differentiation of CD4 + helper cells. In this study, we aimed to investigate the immunomodulatory effects of ursolic acid derivatives (methyl 3β-hydroxyurs-12-en-28-oate (AUD1) and methyl 3β-acetoxyurs-12-en-28-oate (AUD2)) in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein peptide (MOG_35-55) in C57BL/6 mice. On the 15th day post-induction (dpi), the mice were treated with AU, AUD1, or AUD2 (50 mg/kg intraperitoneally per day) for six days. Clinical signs were monitored until 21 dpi, and parameters were assessed in the spinal cord, lymph nodes, and brain at 21 dpi. The results showed that both derivatives similarly attenuated the clinical signs of EAE and reduced inflammation and demyelination in the spinal cord. In addition, they reduced the number of pro-inflammatory cells in the brain, the level of IL-1β, TNF, and IFN-γ in the spinal cord, and, in the periphery, promoted the regulation of pro-inflammatory cells. In conclusion, regulating cells in the periphery and reducing the number of pro-inflammatory cells in the CNS, with AUD1 and AUD2, culminated in the efficacy of the clinical parameters presented in EAE, suggesting a therapeutic potential for treating MS.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"166"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753497","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":"Protective effects of alpha-lipoic acid on memory deficit induced by repeated doses of solifenacin in mice: the role of nitro-oxidative stress.","authors":"Leonardo Pimentel Dantas, Emanuel Carneiro de Vasconcelos, Carla da Silva Cunha, Pauliane Valeska Chagas Batista, Morgana Carla Souza Torres, Caren Nádia Soares de Sousa, Gabriel Angelo de Aquino, Manuel Alves Dos Santos Junior, Pedro Henrique Freitas de Rezende, Wilson Silva de Vasconcelos, Manoel Cláudio Azevedo Patrocinio, Silvânia Maria Mendes Vasconcelos","doi":"10.1007/s11011-025-01586-x","DOIUrl":"https://doi.org/10.1007/s11011-025-01586-x","url":null,"abstract":"<p><p>Solifenacin (Sol) is one of the most used antimuscarinics for the treatment of bladder dysfunction and there are no conclusive studies on its effects on learning and memory after long-term use. Since substances with antioxidant action, such as alpha-lipoic acid (ALA), have shown protective action in memory deficit and Alzheimer's disease, we decided to study the effects of Sol alone or associated with ALA in behavioral tests of memory and its relation to nitro-oxidative stress in different brain areas. Mice received saline or Sol p.o. for 14 or 28 days. ALA groups received: (a) saline + ALA, (b) Sol for 14 days and Sol + ALA from the 15th to the 28th days and, (c) Sol + ALA for 28 days. Behavioral tests were performed and oxidative changes (lipid peroxidation) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were also determined. Sol produced memory alterations in the mice, reducing the step-down latency and the recognition index in the novel object recognition test. Sol also increased lipid peroxidation in PFC, HC and ST and nitrite levels in the HC. On the other hand, ALA associated with Sol was able to restrict the effects caused by Sol alone, both in relation to nitro-oxidative parameters and in relation to behavioral tests. Taken together, our data suggest that ALA can be administered as an adjunctive drug in patients requiring prolonged use of Sol to mitigate these adverse central nervous system effects. However, clinical studies need to be performed to corroborate preclinical research.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"165"},"PeriodicalIF":3.2,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735969","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":"Sex-specific modulation of FOLR1 and its cycle enzyme genes in Alzheimer's disease brain regions.","authors":"Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Michele Vecchio, Manlio Vinciguerra, Kaj Blennow, Henrik Zetterberg, Michelino Di Rosa","doi":"10.1007/s11011-025-01578-x","DOIUrl":"https://doi.org/10.1007/s11011-025-01578-x","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive and functional decline. Its incidence increases significantly with age and is more prevalent in women than men. We investigated the folate receptor alpha (FOLR1) gene expression levels in the central nervous system (CNS) of AD and non-demented healthy control (NDHC) subjects. Our cohort included 3,946 samples: 2,391 NDHC and 1,555 AD patients, stratified by brain region, age, and sex. Interestingly, a significant increase in FOLR1 expression was observed only in females with AD compared to NDHC females. Furthermore, we found that FOLR1 expression was differentially increased in the prefrontal cortex (PFC) and diencephalon (DIE) only in AD females. Moreover, in females, genes involved in the folic acid (FA) cycle that drives DNA synthesis were significantly modulated. In contrast, in males, downregulation of TYMS effectively blocks the completion of the cycle, thereby preventing downstream DNA synthesis. Tissue Transcriptome Deconvolution (TTD) analysis revealed astrocytes and endothelial cells associated with FOLR1 expression in both AD males and females. Gene Ontology analysis supported these findings, showing enrichment in processes aligned with these cell types. Positive correlations between brain FOLR1 expression and markers for astrocytes (glial fibrillary acidic protein) and endothelial cells (CD31) provided further validation. Our findings suggest a potential role for sex-dependent FOLR1 expression and its association with specific brain regions and cellular processes in AD.</p>","PeriodicalId":18685,"journal":{"name":"Metabolic brain disease","volume":"40 4","pages":"163"},"PeriodicalIF":3.2,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735986","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}