Frontiers in Molecular Biosciences最新文献

{"title":"Clinical, phenotype and genotype correlations in primary ciliary dyskinesia suspected children in Egypt.","authors":"Hoda Rizk, Rim Hjeij, Mohammad Al-Haggar, Bernd Dworniczak, Dominik Otto, Heike Olbrich, Engy Osman, Heymut Omran, Tarek Eldesoky","doi":"10.3389/fmolb.2025.1641739","DOIUrl":"10.3389/fmolb.2025.1641739","url":null,"abstract":"<p><strong>Introduction: </strong>Primary ciliary dyskinesia (PCD) is a rare hereditary disorder affecting mucociliary clearance due to ciliary dysfunction. This study aimed to confirm PCD diagnosis in clinically suspected Egyptian individuals and assess genotype-phenotype correlations.</p><p><strong>Methods: </strong>73 PCD-suspected individuals underwent clinical examination, radiological evaluation (chest and sinus CT), and Next-Generation Sequencing (NGS) for a PCD multigene panel. Immunofluorescence (IF) analysis was used to confirm the pathogenicity of identified variants.</p><p><strong>Results: </strong>Consanguinity was reported in 91.9% of cases, with delayed diagnoses spanning 1-18 years. All individuals exhibited a chronic wet cough; 97.3% experienced nasal congestion, 86.5% chronic sinusitis, 75.7% recurrent otitis media, 37.8% finger clubbing, and 24.3% situs abnormalities. Bronchiectasis was demonstrated in 70.3%, and 18.9% had undergone lobectomies. 37 children carried 26 distinct variants in 16 PCD-related genes (50.7%). Defects were found in outer dynein arms (32%), central pair (19%), radial spokes (16%), ciliogenesis (14%), nexin-dynein regulatory complexes (11%), and other ciliary processes (8%). Moreover, IF analysis revealed the deficiency of corresponding ciliary proteins confirming the pathogenicity of the variants.</p><p><strong>Discussion: </strong>Genetic testing confirmed PCD in 50.7% of cases; based on published TEM-detectable ultrastructural defects, only 40.5% would likely have been detectable by TEM alone, highlighting the need for advanced diagnostics.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1641739"},"PeriodicalIF":3.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomic profiling reveals systemic serum lipid remodeling induced by dexamethasone in mice.","authors":"Aiping Zhang, Zhao Wang, Jianjian Ji","doi":"10.3389/fmolb.2025.1644637","DOIUrl":"10.3389/fmolb.2025.1644637","url":null,"abstract":"<p><strong>Background: </strong>Dexamethasone is a commonly used glucocorticoid medication in pediatrics. However, dexamethasone is associated with some side effects, such as dyslipidemia. This study aimed to explore the effects of dexamethasone on the serum lipidome.</p><p><strong>Methods: </strong>We utilized Exactive Orbitrap-MS technology to assess the effects of dexamethasone intervention on serum lipids in mice.</p><p><strong>Results: </strong>Unbiased Principal Component Analysis (PCA) revealed that dexamethasone intervention significantly induced changes in serum lipids in mice, and after a 7-day washout period (equivalent to 28 drug half-lives), changes of lipids in the serum were still existed compared with those in the control groups. After 4 days of dexamethasone injection, significant changes were observed, including 16 increased lipids, and 1 decreased lipid in the serum compared with those in the control groups. After a 7-day washout period, some of lipids in the serum were still changed, including 5 increased lipids, such as Acylcarnitines (CAR), ceramides (Cer), diacylglycerophosphates (DG), lysophosphatidylglycerol (LPG) and phosphatidylglycerol (PG), 1 decreased lipid, hexosylceramides (HexCer), indicating dexamethasone may result in long-term changes of lipids in the serum.</p><p><strong>Discussion: </strong>In conclusion, utilizing a lipidomics method, we provide the first complete proof that dexamethasone intervention generates extensive modification of the serum lipidome.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1644637"},"PeriodicalIF":3.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global DNA-methylation in quantitative epigenetics: orbitrap mass spectrometry.","authors":"Janine F M Otto, Georg Pohnert, Thomas Wichard, Michael Bauer, Anne Busch, Nico Ueberschaar","doi":"10.3389/fmolb.2025.1681568","DOIUrl":"10.3389/fmolb.2025.1681568","url":null,"abstract":"<p><p>DNA methylation is the most common epigenetic modification in both prokaryotic and eukaryotic genomes. Here we present a method based on highly efficient acid-hydrolysis of DNA, liquid chromatography, and detection by mass spectrometry to accurately quantify cytosine methylation in highly methylated DNA samples. This approach enables direct, rapid, cost-efficient, and sensitive quantification of the methyl-modified nucleobase 5-methylcytosine and 6-methyl adenine, along with their unmodified nucleobases. In contrast to standard sequencing techniques, our method only gives quantitative information on the overall degree of methylation, but it requires only small amounts of DNA and is not dependent on lengthy bioinformatic analyses. Our method allows rapid, global methylome analysis and quantifies a central epigenetic marker. In a proof-of-principle study, we show that it can also be extended to the monitoring of other DNA modifications, such as methylated adenine. Uncomplicated data analysis facilitates a quick and straightforward comparison of DNA methylation across biological contexts. In a case study, we also successfully identified changes in methylation signatures in the marine macroalga <i>Ulva mutabilis</i> \"slender\". The advantage of global methylation analysis compared to sequencing allows for generating fast prior knowledge on which sample sequencing is senseful. The great benefit of the presented method is the speed and accuracy of the global methylation analysis, which is independent of the total methylation rate and gives accurate results, whereas competitive based on enzymatic digestion might fail.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1681568"},"PeriodicalIF":3.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transformation of acute kidney injury to chronic kidney disease: the interaction between mitophagy and NLRP3 inflammasome.","authors":"Yixin Zhu, Chenxi Lv, Yanheng Qiao, Hanqi Yang, Wentong Lin, Xuchen Wang, Yueqi Zhang, Bo Yang","doi":"10.3389/fmolb.2025.1643829","DOIUrl":"10.3389/fmolb.2025.1643829","url":null,"abstract":"<p><p>Acute kidney injury (AKI) and chronic kidney disease (CKD) are closely interrelated renal disorders, where AKI frequently progresses to CKD, resulting in irreversible loss of renal function. In recent years, the roles of the NLRP3 inflammasome and mitophagy in the AKI-to-CKD transition have attracted significant attention. As a crucial component of the innate immune system, the NLRP3 inflammasome promotes AKI-to-CKD progression by mediating inflammatory responses and cellular pyroptosis during renal injury. Conversely, mitophagy exerts renoprotective effects through the selective removal of damaged mitochondria, maintenance of cellular homeostasis, and alleviation of inflammation and oxidative stress. Studies demonstrate that NLRP3 activation is closely associated with mitochondrial dysfunction, while mitophagy can suppress NLRP3 activation by clearing damaged mitochondria, establishing a negative feedback regulatory mechanism. During the AKI phase, mitochondrial damage and excessive NLRP3 activation exacerbate renal tubular epithelial cell injury and inflammatory responses. Concurrently, persistent NLRP3 activation and impaired mitophagy lead to chronic inflammation and fibrosis, accelerating the transition from AKI to CKD. Therefore, targeting the NLRP3 inflammasome and modulating mitophagy may emerge as novel therapeutic strategies for AKI-to-CKD transition. This review focuses on elucidating the molecular mechanisms between mitophagy and the NLRP3 inflammasome, along with related targeted therapies, to provide new insights for preventing AKI progression to CKD.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1643829"},"PeriodicalIF":3.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between membrane-bound streptococcal alpha-enolase and human plasminogen captured through cryogenic-electron microscopy.","authors":"Sheiny Tjia-Fleck, Bradley M Readnour, Zhong Liang, Yetunde A Ayinuola, Francis J Castellino","doi":"10.3389/fmolb.2025.1666748","DOIUrl":"10.3389/fmolb.2025.1666748","url":null,"abstract":"<p><p>Certain invasive strains of the Gram-positive bacterium <i>Streptococcus pyogenes</i> exploit human plasminogen (hPg) to promote tissue invasion and pathogenesis. hPg is a single-chain multi-modular zymogen containing five kringle domains (K1-K5), four of which interact with lysine or pseudo-lysine residues on binding partners, positioning hPg for activation to plasmin and enhancing bacterial dissemination. The major hPg binding protein in <i>S. pyogenes</i> is the multicopy surface-resident M-protein, or other surface proteins, such as the homooctameric glycolytic enzyme, enolase (SEn). SEn lacks features for direct translocation from the cytoplasm to the bacterial surface, and it is unclear how Sen is translocated to the bacterial surface. Additionally, the mechanism by which SEn binds hPg is poorly understood. In this study, we show that SEn is exported via lipid microvesicles (MV), likely originating from the cytosolic membrane. Using cryogenic-electron microscopy, we provide a high-resolution (<3.4 Å) map of SEn reconstituted into dioleoyl phosphatidylglycerol (DOPG) liposomes, which serves as our MV model. The Sen-DOPG map reveals that two subunits of the SEn octamer are exposed to the extracellular medium, while six remain inserted within the membrane or vesicle interior. However, this interaction does not induce a conformational change in hPg, which remains in a closed conformation, thereby limiting the SEn stimulatory effect on many hPg activators, except for host tissue-type plasminogen activator (tPA). Instead, the ability of SEn to bind tPA is the primary factor driving enhanced hPg activation. These findings highlight a novel mechanism by which MV-associated SEn promotes hPg activation preferentially through tPA, independent of a hPg conformational rearrangement.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1666748"},"PeriodicalIF":3.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibrinogen glycosylation and glycation: molecular insights into thrombosis and vascular disease.","authors":"Serena Borghi, Francesca Nencini, Elvira Giurranna, Ilenia Barbaro, Niccolò Taddei, Claudia Fiorillo, Matteo Becatti","doi":"10.3389/fmolb.2025.1680332","DOIUrl":"10.3389/fmolb.2025.1680332","url":null,"abstract":"<p><p>Fibrinogen, a key protein in blood coagulation, undergoes two distinct post-translational modifications (PTMs): glycosylation and glycation. Glycosylation is an enzymatic, tightly regulated process, whereas glycation occurs non-enzymatically under hyperglycemic conditions. Emerging evidence highlights the role of these modifications in cardiovascular risk. This review provides a comprehensive overview of how fibrinogen glycosylation and glycation contribute to altered haemostatic profiles and increased cardiovascular risk. Evidence is presented from inherited fibrinogen disorders, liver disease, diabetes, and chronic conditions such as end-stage renal disease. Additionally, the potential use of glycosylation and glycation patterns as diagnostic or prognostic biomarkers in cardiovascular disease is discussed. Overall, changes in fibrinogen's glycosylation and glycation profiles may serve as important markers for cardiovascular risk assessment in many diseases, offering insights into the molecular mechanisms underlying these conditions.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1680332"},"PeriodicalIF":3.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of TGFβ1-Induced activin A gene expression in kidney mesangial cells.","authors":"Asfia Soomro, Ifeanyi Kennedy Nmecha, Jackie Trink, Renzhong Li, Joan C Krepinsky","doi":"10.3389/fmolb.2025.1607043","DOIUrl":"10.3389/fmolb.2025.1607043","url":null,"abstract":"<p><strong>Introduction: </strong>The cytokine activin A is emerging as an important regulator of kidney fibrosis. Its expression, negligible in normal kidney, is significantly increased in various fibrotic kidney diseases. TGFβ1 is a cytokine belonging to the same family, which is well established to be a central mediator of kidney fibrosis. Although targeting TGFβ1 therapeutically is not feasible due to its homeostatic roles, we previously showed that activin A is upregulated by, and mediates the profibrotic effects of, TGFβ1.</p><p><strong>Methods: </strong>We investigated the transcriptional regulation of activin A by TGFβ1 in primary kidney mesangial cells (MC). Cells were transfected with a luciferase reporter construct containing the activin A promoter or a series of deletion constructs. Guided by MatInspector, key TGFβ1-responsive consensus elements were identified.</p><p><strong>Results: </strong>TGFβ1 increased transcription of the activin A subunit <i>inhba</i>. Using a series of deletion constructs of the <i>inhba</i> promoter, we identified a critical regulatory region located 350bp from the transcription start site that is responsive to TGFβ1. Analysis of this region for transcription factor regulatory elements, coupled with mutation analyses and transcription factor downregulation with siRNA, showed that Stat5 and FoxP1, but not Sox9, regulate <i>inhba</i> transcription by TGFβ1. Interestingly, although no consensus binding site in this region was identified for Smad3, a well-established mediator of TGFβ1 signaling, both a Smad3 inhibitor and use of MC isolated from Smad3 knockout kidneys, showed its requirement for the TGFβ1 response. We further identified a CT microsatellite just upstream of 350bp which suppressed promoter activity.</p><p><strong>Conclusion: </strong>These findings provide insight into potential therapeutic targets for activin A targeting and attenuation of kidney fibrosis.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1607043"},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling the mechanistic nexus: how micronutrient enrichment shapes brain function, and cognitive health.","authors":"Siddhartha Das, Pradipta Banerjee, Sudipta Jana, Hemanshu Mondal","doi":"10.3389/fmolb.2025.1623547","DOIUrl":"10.3389/fmolb.2025.1623547","url":null,"abstract":"<p><p>Minerals, vitamins, and trace elements are examples of micronutrients essential for psychological wellbeing and brain function. Severe disorders may result from their deficiency or, conversely, from an excess of them. Recent studies have indicated that the etiopathogenesis of certain neurological disorders may involve chronically elevated micronutrient levels. Physiological functions, such as energy metabolism, neurotransmitter synthesis, and antioxidant defence, are regulated by these vital nutrients and are essential for optimal neuronal activity. According to new research, micronutrient enrichment, whether through diet or supplements, can have a significant impact on cognitive function, neuroplasticity, and brain development. Cognitive decline, memory loss, and attention problems are linked to deficiencies in essential micronutrients, including vitamin B12, iron, zinc, and omega-3 fatty acids. Tailored micronutrient therapies have shown promise in reducing age-related cognitive decline and enhancing mental function in both healthy individuals and those at greater risk. This manuscript emphasizes the growing research linking micronutrient status to cognitive health. It also highlights the importance of maintaining a balanced diet and following appropriate supplementation practices to optimize brain function throughout life.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1623547"},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated analysis and experimental validation of E2F2 as a potential prognostic biomarker and its oncogenic roles in serous ovarian cancer.","authors":"Fengyin Jiang, He Fei, Lina Yang, Rujun Chen, Liwen Zhang","doi":"10.3389/fmolb.2025.1661558","DOIUrl":"10.3389/fmolb.2025.1661558","url":null,"abstract":"<p><strong>Background: </strong>This study evaluated the prognostic role of E2F transcription factor 2 (E2F2) in serous ovarian cancers (SOCs) and explored its biological functions, immune cell infiltration links, and therapeutic implications.</p><p><strong>Methods: </strong>Integrating TCGA/Genotype-Tissue Expression (GTEx) data, we used bioinformatics tools (ssGSEA, Immunophenoscore, and oncoPredict) to analyze pathways and treatment responses. Validation involved RT-qPCR, Western blot analysis, cytotoxicity, and transwell assays.</p><p><strong>Results: </strong>E2F2 was upregulated in SOC tumors, correlating with poorer overall/disease-free survival and higher tumor grade. Five cell-cycle-related genes (<i>ORC1</i>, <i>RAD54L</i>, <i>CCNF</i>, <i>NCAPH</i>, and <i>HASPIN</i>) showed strong co-expression. A pathway analysis of 808 differentially expressed genes linked E2F2 to immune cell recruitment, including CD4⁺ T cells, NK cells, and Tregs; low E2F2 levels were associated with higher immune scores. High E2F2 predicted sensitivity to chemotherapy/targeted therapy, while low E2F2 correlated with anti-CTLA4 responsiveness. <i>In vitro</i>, E2F2 promoted metastasis.</p><p><strong>Conclusion: </strong>High E2F2 expression marks poor prognosis and immune cell infiltration in SOCs and thus acts as an independent risk factor. It may serve as a potential biomarker for diagnosis, patient stratification, and guiding personalized therapy. Further research could enhance SOC management.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1661558"},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unleashing the immune modulatory potential of <i>Leishmania amazonensis-</i>derived extracellular vesicles in American cutaneous leishmaniasis.","authors":"Bruna Eugênia de Freitas, Armanda Rodrigues, Joana Palma-Marques, Juliana Inês Weber, Ana Valério-Bolas, Rodrigo Pedro Soares, Ana Claudia Torrecilhas, Micheli Ferla, Munira Muhammad Abdel Baqui, Raul Alexander Gonzales Cordova, Graça Alexandre-Pires, Isabel Pereira da Fonseca, Hélida Monteiro de Andrade, Gabriela Santos-Gomes","doi":"10.3389/fmolb.2025.1593363","DOIUrl":"10.3389/fmolb.2025.1593363","url":null,"abstract":"<p><strong>Introduction: </strong>American cutaneous leishmaniasis (ACL) constitutes a neglected skin disease that causes severe disability and significant social stigma for millions of people each year. This parasitic infection is caused by several species of the protozoan <i>Leishmania</i>, including <i>Leishmania amazonensis</i>. There is therefore an urgent need to develop effective new tools to control ACL, primarily due to the limitations of current prophylactic and therapeutic strategies, which are exacerbated by the growing burden of the disease and its social impact. In recent years, scientific research has focused on extracellular vesicles (EVs), which are lipid-enclosed rounded nanostructures that carry macromolecules to recipient cells and are part of eukaryotic biology. The role of <i>Leishmania</i>-derived EVs in host pathogenesis has attracted considerable attention among researchers, with studies suggesting that EVs may play a key role in modulating the host immune response. Therefore, this study examined the immunogenicity and protein cargo of EVs shed by <i>L. amazonensis,</i> exploring their effect on immune activation in the murine macrophages (MΦs) lineage.</p><p><strong>Methods: </strong>Nanoparticle tracking analysis, microscopy, proteomic methodologies, colorimetric assays, serological immune methods, PCR, and multiparametric flow cytometry were employed.</p><p><strong>Results: </strong>EVs derived from <i>L. amazonensis</i> cultured promastigotes contain key components, such as the 63 kDa surface glycoprotein, intracellular heat shock protein 70, and α-type proteasome subunit, which may be involved in parasite survival. Moreover, EVs are recognized by mouse- and human-specific antibodies, indicating that they have the potential to elicit humoral immune responses and can be inactivated by host-specific antibodies. Depending on the concentration, EVs can drive MΦs to express MHC molecules that are essential for antigen presentation to T lymphocytes, thereby being able to promote a cellular immune response. EVs favor IL-1β⁺MΦs contraction, and low nitric oxide production, and activate the arginase pathway to produce urea along with the generation of proinflammatory cytokines. This MΦs modulation may support parasite control through the specific activation of T cells while preserving skin homeostasis, thereby reducing the pathology associated with <i>L. amazonensis</i> infection, which causes ACL and leads to the development of chronic disease.</p><p><strong>Discussion: </strong>Thus, this study's findings suggest that although <i>L. amazonensis</i>-derived EVs can trigger MΦs activation, favoring a pro-inflammatory immune response, they also have the potential to ensure parasite survival while limiting host pathogenesis. This can be advantageous for parasite transmission and essential for completing the parasite life cycle.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1593363"},"PeriodicalIF":3.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}