Cellular and Molecular Life Sciences最新文献

{"title":"Integration of CRISPR/dCas9-Based methylation editing with guide positioning sequencing identifies dynamic changes of mrDEGs in breast cancer progression.","authors":"Baolong Zhang, Jin Li, Wenqiang Yu","doi":"10.1007/s00018-024-05562-z","DOIUrl":"10.1007/s00018-024-05562-z","url":null,"abstract":"<p><p>Dynamic changes in DNA methylation are prevalent during the progression of breast cancer. However, critical alterations in aberrant methylation and gene expression patterns have not been thoroughly characterized. Here, we utilized guide positioning sequencing (GPS) to conduct whole-genome DNA methylation analysis in a unique human breast cancer progression model: MCF10 series of cell lines (representing benign/normal, atypical hyperplasia, and metastatic carcinoma). By integrating with mRNA-seq and matched clinical expression data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), six representative methylation-related differentially expressed genes (mrDEGs) were identified, including CAVIN2, ARL4D, DUSP1, TENT5B, P3H2, and MMP28. To validate our findings, we independently developed and optimized the dCas9-DNMT3L-DNMT3A system, achieving a high efficiency with a 98% increase in methylation at specific sites. DNA methylation levels significantly increased for the six genes, with CAVIN2 at 67.75 ± 1.05%, ARL4D at 53.29 ± 6.32%, DUSP1 at 57.63 ± 8.46%, TENT5B at 44.00 ± 5.09%, P3H2 at 58.50 ± 3.90%, and MMP28 at 49.60 ± 5.84%. RT-qPCR confirmed an inverse correlation between increased DNA methylation and gene expression. Most importantly, we mimicked tumor progression in vitro, demonstrating that transcriptional silencing of the TENT5B promotes cell proliferation in MCF10A cells owing to the crosstalk between hypermethylation and histone deacetylation. This study unveils the practical implications of DNA methylation dynamics of mrDEGs in reshaping epigenomic features during breast cancer malignant progression through integrated data analysis of the methylome and transcriptome. The application of the CRISPR/dCas9-based methylation editing technique elucidates the regulatory mechanisms and functional roles of individual genes within the DNA methylation signature, providing valuable insights for understanding breast cancer pathogenesis and facilitating potential therapeutic approaches in epigenome editing for patients with breast cancer.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"46"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing of the carotid artery and femoral artery of rats exposed to hindlimb unloading.","authors":"Chengfei Li, Yikai Pan, Yuan Wang, Xi Li, Yateng Tie, Shuhan Li, Ruonan Wang, Xingcheng Zhao, Jieyi Fan, Xianchun Yan, Yongchun Wang, Xiqing Sun","doi":"10.1007/s00018-024-05572-x","DOIUrl":"10.1007/s00018-024-05572-x","url":null,"abstract":"<p><strong>Background: </strong>Prolonged spaceflight is known to cause vascular deconditioning and remodeling. Tail suspension, a widely used spaceflight analog, is reported to result in vascular remodeling of rats. However, little is known about the cellular atlas of the heterogeneous cells of CA and FA from hindlimb-unloaded rats.</p><p><strong>Methods: </strong>Firstly, we leveraged scRNA-seq to perform clustering analysis to identify diverse cell populations and sub-clusters within CA and FA from rats subjected to 3 months of hindlimb unloading. The dysregulated genes specific for artery types and cell types in HU group compared to Con were unraveled. Then R package \"Cellchat\" was used to reveal ligand-receptor cellular communication. At last, the TF network analysis was performed using the SCENIC R package to predict the pivotal TFs in rat artery remodeling induced by hindlimb unloading.</p><p><strong>Results: </strong>Clustering analysis identified ECs, SMCs, fibroblasts, and a spectrum of immune cells, as well as neuronal and stem cells. Notably, an increased percentage of ECs in the CA and a diminished proportion of SMCs in both CA and FA were observed following tail suspension. Intersection of dysregulated genes specific for artery type and cell type after tail suspension revealed several gene sets involved in ECM remodeling, inflammation, vasoconstriction, etc. Fibroblasts, in particular, exhibited the most significant gene expression variability, highlighting their plasticity. Subclustering within ECs, SMCs and fibroblasts revealed specialized subsets engaged in processes such as EndoMT and cell cycle checkpoint regulation. Additionally, enhanced intercellular interactions among major cell types, especially between SMC and fibroblast, underscored the importance of cell communication in vascular remodeling. Several TFs were identified as potentially influential in the vascular remodeling process under simulated microgravity conditions.</p><p><strong>Conclusions: </strong>This study presents the first cellular atlas of the conductive arteries in hindlimb-unloaded rats, revealing a spectrum of dysregulated gene profiles. The identification of the subclusters of ECs, SMCs and fibroblasts, cellular communication analysis and transcription factors prediction are also included in this work. The findings provide a reference for future research on vascular deconditioning following long-duration spaceflight.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"50"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of psychedelics on opioid use disorder: a scoping review of preclinical studies.","authors":"Alejandra Pulido-Saavedra, Henrique Nunes Pereira Oliva, Tiago Paiva Prudente, Razi Kitaneh, Eric J Nunes, Colleen Fogg, Melissa C Funaro, Jeremy Weleff, Anahita Bassir Nia, Gustavo A Angarita","doi":"10.1007/s00018-024-05519-2","DOIUrl":"10.1007/s00018-024-05519-2","url":null,"abstract":"<p><p>The current opioid crisis has had an unprecedented public health impact. Approved medications for opioid use disorder (OUD) exist, yet their limitations indicate a need for innovative treatments. Limited preliminary clinical studies suggest specific psychedelics might aid OUD treatment, though most clinical evidence remains observational, with few controlled trials. This review aims to bridge the gap between preclinical findings and potential clinical applications, following PRISMA-ScR guidelines. Searches included MEDLINE, Embase, Scopus, and Web of Science, focusing on preclinical in vivo studies involving opioids and psychedelics in animals, excluding pain studies and those lacking control groups. Forty studies met criteria, covering both classic and non-classic psychedelics. Most studies showed that 18-methoxycoronaridine (18-MC), ibogaine, noribogaine, and ketamine could reduce opioid self-administration, alleviate withdrawal symptoms, and change conditioned place preference. However, seven studies (two on 2,5-dimethoxy-4-methylamphetamine (DOM), three on ibogaine, one on 18-MC, and one on ketamine) showed no improvement over controls. A methodological quality assessment rated most of the studies as having unclear quality. Interestingly, most preclinical studies are limited to iboga derivatives, which were effective, but these agents may have higher cardiovascular risk than other psychedelics under-explored to date. This review strengthens support for translational studies testing psychedelics as potential innovative targets for OUD. It also suggests clinical studies need to include a broader range of agents beyond iboga derivatives but can also explore several ongoing questions in the field, such as the mechanism of action behind the potential therapeutic effect, safety profiles, doses, and frequency of administrations needed.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"49"},"PeriodicalIF":6.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palmitate potentiates the SMAD3-PAI-1 pathway by reducing nuclear GDF15 levels.","authors":"Marta Montori-Grau, Emma Barroso, Javier Jurado-Aguilar, Mona Peyman, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera","doi":"10.1007/s00018-024-05571-y","DOIUrl":"https://doi.org/10.1007/s00018-024-05571-y","url":null,"abstract":"<p><p>Nuclear growth differentiation factor 15 (GDF15) reduces the binding of the mothers' against decapentaplegic homolog (SMAD) complex to its DNA-binding elements. However, the stimuli that control this process are unknown. Here, we examined whether saturated fatty acids (FA), particularly palmitate, regulate nuclear GDF15 levels and the activation of the SMAD3 pathway in human skeletal myotubes and mouse skeletal muscle, where most insulin-stimulated glucose use occurs in the whole organism. Human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15^-/- mice fed a standard (STD) or a high-fat (HFD) diet were subjected to a series of studies to investigate the involvement of lipids in nuclear GDF15 levels and the activation of the SMAD3 pathway. The saturated FA palmitate, but not the monounsaturated FA oleate, increased the expression of GDF15 in human myotubes and, unexpectedly, decreased its nuclear levels. This reduction was prevented by the nuclear export inhibitor leptomycin B. The decrease in nuclear GDF15 levels caused by palmitate was accompanied by increases in SMAD3 protein levels and in the expression of its target gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1). HFD-fed Gdf15^-/- mice displayed aggravated glucose intolerance compared to HFD-fed WT mice, with increased levels of SMAD3 and PAI-1 in the skeletal muscle. The increased PAI-1 levels in the skeletal muscle of HFD-fed Gdf15^-/- mice were accompanied by a reduction in one of its targets, hepatocyte growth factor (HGF)α, a cytokine involved in glucose metabolism. Interestingly, PAI-1 acts as a ligand of signal transducer and activator of transcription 3 (STAT3) and the phosphorylation of this transcription factor was exacerbated in HFD-fed Gdf15^-/- mice compared to HFD-fed WT mice. At the same time, the protein levels of insulin receptor substrate 1 (IRS-1) were reduced. These findings uncover a potential novel mechanism through which palmitate induces the SMAD3-PAI-1 pathway to promote insulin resistance in skeletal muscle by reducing nuclear GDF15 levels.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"43"},"PeriodicalIF":6.2,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1 and HIF-2 in cancer: structure, regulation, and therapeutic prospects.","authors":"Yi Shi, Daniele M Gilkes","doi":"10.1007/s00018-024-05537-0","DOIUrl":"https://doi.org/10.1007/s00018-024-05537-0","url":null,"abstract":"<p><p>Hypoxia, or a state of low tissue oxygenation, has been characterized as an important feature of solid tumors that is related to aggressive phenotypes. The cellular response to hypoxia is controlled by Hypoxia-inducible factors (HIFs), a family of transcription factors. HIFs promote the transcription of gene products that play a role in tumor progression including proliferation, angiogenesis, metastasis, and drug resistance. HIF-1 and HIF-2 are well known and widely described. Although these proteins share a high degree of homology, HIF-1 and HIF-2 have non-redundant roles in cancer. In this review, we summarize the similarities and differences between HIF-1α and HIF-2α in their structure, expression, and DNA binding. We also discuss the canonical and non-canonical regulation of HIF-1α and HIF-2α under hypoxic and normal conditions. Finally, we outline recent strategies aimed at targeting HIF-1α and/or HIF-2α.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"44"},"PeriodicalIF":6.2,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria.","authors":"Wanting Xu, Lei Dong, Ji Dai, Lu Zhong, Xiao Ouyang, Jiaqian Li, Gaoqing Feng, Huahua Wang, Xuan Liu, Liying Zhou, Qin Xia","doi":"10.1007/s00018-024-05556-x","DOIUrl":"10.1007/s00018-024-05556-x","url":null,"abstract":"<p><p>Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through the continuous accumulation of misfolded proteins and damaged organelles. This review delineates the roles of two complementary and synergistic degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, in the degradation of misfolded proteins and damaged organelles for intracellular recycling. We emphasize the interconnected decision-making processes of degradation systems in maintaining cellular homeostasis, such as the biophysical state of substrates, receptor oligomerization potentials (e.g., p62), and compartmentalization capacities (e.g., membrane structures). Mitochondria, the cellular hubs for respiration and metabolism, are implicated in tumorigenesis. In the subsequent sections, we thoroughly examine the mechanisms of mitochondrial quality control (MQC) in preserving mitochondrial homeostasis in human cells. Notably, we explored the relationships between mitochondrial dynamics (fusion and fission) and various MQC processes-including the UPS, mitochondrial proteases, and mitophagy-in the context of mitochondrial repair and degradation pathways. Finally, we assessed the potential of targeting MQC (including UPS, mitochondrial molecular chaperones, mitochondrial proteases, mitochondrial dynamics, mitophagy and mitochondrial biogenesis) as cancer therapeutic strategies. Understanding the mechanisms underlying mitochondrial homeostasis may offer novel insights for future cancer therapies.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"42"},"PeriodicalIF":6.2,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMP4 regulates differentiation of nestin-positive stem cells into melanocytes.","authors":"Rongfang Xie, Miaomiao Li, Xusheng Wang, Zhongjie Liu","doi":"10.1007/s00018-024-05564-x","DOIUrl":"10.1007/s00018-024-05564-x","url":null,"abstract":"<p><p>Hair follicle (HF) development and pigmentation are complex processes governed by various signaling pathways, such as TGF-β and FGF signaling pathways. Nestin + (neural crest like) stem cells are also expressed in HF stem cells, particularly in the bulge and dermal papilla region. However, the specific role and differentiation potential of these Nestin-positive cells within the HF remain unclear, especially regarding their contribution to melanocyte formation and hair pigmentation. Bone morphogenetic protein 4 (BMP4), members of the TGFβ family, has been implicated in regulating HF growth, coloration, and related cellular behaviors. Its role in directing Nestin-positive cells toward a melanocytic lineage has yet to be fully explored. In this study, mouse HF organoids were constructed and shown to be an ideal model for studying HF growth and development in vitro. Using this model as a basis, we demonstrated that BMP4 controls HF coloration as well as its length, number, and even size. Furthermore, Nestin-positive cells in the HF-especially those in the bulge region-differentiate into melanocytes, which produce the pigments that give HF its color under BMP4 stimulation. The resulting increase in pigmentation within the mouse HF organoids underscores that BMP4 has a major regulatory role in the formation of melanocytes from Nestin-positive stem cells. This research provides insights into the cellular mechanisms underlying hair pigmentation and suggests potential therapeutic applications for pigmentation disorders.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"41"},"PeriodicalIF":6.2,"publicationDate":"2025-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11725548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The protective effects of liraglutide in reducing lipid droplets accumulation and myocardial fibrosis in diabetic cardiomyopathy.","authors":"Chien-Yin Kuo, Sing-Hua Tsou, Edy Kornelius, Kuei-Chuan Chan, Kai-Wei Chang, Jung-Chi Li, Chien-Ning Huang, Chih-Li Lin","doi":"10.1007/s00018-024-05558-9","DOIUrl":"10.1007/s00018-024-05558-9","url":null,"abstract":"<p><strong>Background: </strong>Diabetes is a primary contributor to diabetic cardiomyopathy (DbCM), which is marked by metabolic imbalances such as elevated blood glucose and lipid levels, leading to significant structural and functional alterations in the myocardium. Elevated free fatty acids (FFAs) and hyperglycemia play critical roles in DbCM development, with FFAs inducing insulin resistance in cardiomyocytes and promoting lipid accumulation, resulting in oxidative stress and fibrosis. Current research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists may effectively mitigate DbCM, although an effective treatment for this condition remains elusive, and the precise mechanisms of this protective effect are not fully understood.</p><p><strong>Methods: </strong>In this study, we aimed to replicate diabetic glucolipotoxic conditions by treating differentiated H9c2 cells with high glucose and free fatty acids. Additionally, a diabetic cardiomyopathy model was induced in mice through high-fat diets. Both in vitro and in vivo models were used to investigate the protective effects of liraglutide on cardiomyocytes and elucidate its underlying molecular mechanisms.</p><p><strong>Results: </strong>Our findings indicate that liraglutide significantly reduces lipid droplet (LD) formation and myocardial fibrosis, as evidenced by decreased expression of fibrosis markers, including TGF-β1 and collagen types I and III. Liraglutide also enhanced AMP-activated protein kinase (AMPK) activation, which improved mitochondrial function, increased antioxidant gene expression, enhanced insulin signaling, and reduced oxidative stress.</p><p><strong>Conclusions: </strong>These results demonstrate the potential therapeutic role of liraglutide in managing diabetes-related cardiac complications, offering a comprehensive approach to improving cardiac outcomes in patients with diabetes.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"39"},"PeriodicalIF":6.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SLC10A7 regulates O-GalNAc glycosylation and Ca²⁺ homeostasis in the secretory pathway: insights into SLC10A7-CDG.","authors":"Zoé Durin, Aurore Layotte, Willy Morelle, Marine Houdou, Antoine Folcher, Dominique Legrand, Dirk Lefeber, Natalia Prevarskaya, Julia Von Blume, Valérie Cormier-Daire, François Foulquier","doi":"10.1007/s00018-024-05551-2","DOIUrl":"10.1007/s00018-024-05551-2","url":null,"abstract":"<p><p>Glycans are known to be fundamental for many cellular and physiological functions. Congenital disorders of glycosylation (CDG) currently encompassing over 160 subtypes, are characterized by glycan synthesis and/or processing defects. Despite the increasing number of CDG patients, therapeutic options remain very limited as our knowledge on glycan synthesis is fragmented. The emergence of CDG resulting from defects in ER/ Golgi homeostasis makes this even more difficult. SLC10A7 belongs to the SLC10 protein family, known as bile acid and steroid transport family, exhibiting a unique structure. It shows a ubiquitous expression and is linked to negative calcium regulation in cells. The mechanisms by which SLC10A7 deficiency leads to Golgi glycosylation abnormalities are unknown. The present study identifies major O-glycosylation defects in both SLC10A7 KO HAP1 cells and SLC10A7-CDG patient fibroblasts and reveals an increased ER and Golgi calcium contents. We also show that the abundance of COSMC and C1GALT1 is altered in SLC10A7-CDG patient cells, as well as the subcellular Golgi localization of the Ca²⁺-binding Cab45 protein. Finally, we demonstrate that supraphysiological manganese supplementation suppresses the deficient electrophoretic mobility of TGN46 by an aberrant transfer of GalNAc residues, and reveal COSMC Mn²⁺ sensitivity. These findings provide novel insights into the mechanisms of Golgi glycosylation defects in SLC10A7-deficient cells. They show that SLC10A7 is a key Golgi transmembrane protein maintaining the tight regulation of Ca²⁺ homeostasis in the ER and Golgi compartments, both essential for glycosylation.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"40"},"PeriodicalIF":6.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"18 kDa TSPO targeting drives polarized human microglia towards a protective and restorative neurosteroidome profile.","authors":"Lorenzo Germelli, Elisa Angeloni, Eleonora Da Pozzo, Chiara Tremolanti, Martina De Felice, Chiara Giacomelli, Laura Marchetti, Beatrice Muscatello, Elisabetta Barresi, Sabrina Taliani, Federico Da Settimo Passetti, Maria Letizia Trincavelli, Claudia Martini, Barbara Costa","doi":"10.1007/s00018-024-05544-1","DOIUrl":"https://doi.org/10.1007/s00018-024-05544-1","url":null,"abstract":"<p><p>An aberrant pro-inflammatory microglia response has been associated with most neurodegenerative disorders. Identifying microglia druggable checkpoints to restore their physiological functions is an emerging challenge. Recent data have shown that microglia produce de novo neurosteroids, endogenous molecules exerting potent anti-inflammatory activity. Here, the role of neurosteroidogenesis in the modulation of microgliosis was explored in human microglia cells. In particular, CYP11A1 inhibition or TSPO pharmacological stimulation, crucial proteins involved in the rate limiting step of the neurosteroidogenic cascade, were employed. CYP11A1 inhibition led microglia to acquire a dysfunctional and hyperreactive phenotype, while selective TSPO ligands promoted the establishment of an anti-inflammatory one. Analysis of specific neurosteroid levels (neurosteroidome) identified allopregnanolone/pregnanolone as crucial metabolites allowing controlled activation of microglia. Importantly, the neurosteroid shift towards a greater androgenic/estrogenic profile supported the transition from pro-inflammatory to neuroprotective microglia, suggesting the therapeutic potential of de novo microglial neurosteroidogenesis stimulation for neuroinflammatory-related disorders.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"34"},"PeriodicalIF":6.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}