Frontiers in Molecular Biosciences最新文献

{"title":"Uptake of iron from ferrous fumarate can be mediated by clathrin-dependent endocytosis in Hutu-80 cells.","authors":"Agata Tarczykowska, Per Malmberg, Nathalie Scheers","doi":"10.3389/fmolb.2025.1460565","DOIUrl":"10.3389/fmolb.2025.1460565","url":null,"abstract":"<p><p>Iron uptake in the intestinal epithelium is associated with transport of ferrous iron via the DMT1 transporter (SLC11a2; NRAMP2). In later years, uptake of iron from complex sources, such as nanoparticles, has been found to be mediated through endocytosis. Here we propose that iron from the simple salt ferrous fumarate, a common iron supplement, can be absorbed by clathrin-mediated endocytosis. We used siRNA to silence DMT1 transporter expression, pharmacological inhibition of endocytosis, and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) to show that iron uptake from ferrous fumarate can be mediated by both transport via DMT1 and by clathrin-dependent endocytosis in Hutu-80 cells. Iron uptake (ferritin L) from ferrous fumarate (0.5 mM, 24 h) in DMT1 silenced cells was significantly decreased (60% ± 11%) in comparison to iron controls while a 1-h dose of ferrous fumarate (0.5 mM) significantly decreased ferritin L formation in the presence of the clathrin inhibitor chlorpromazine (61% ± 10%, in post-confluent cells and 37% ± 9% in non-confluent cells). A pilot showed a similar trend for Ferritin (H) levels (confluent cells) and for total cellular iron load (non-confluent cells). ToF-SIMS analysis revealed diminished membrane-associated iron load in endocytosis-inhibited ferrous fumarate treated cells. The reported results support a clathrin-mediated endocytosis mechanism for uptake of iron from ferrous fumarate in addition to iron uptake by DMT1. More studies are needed to understand what determines which uptake mechanism are employed and to which extent.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1460565"},"PeriodicalIF":3.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11807817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390269","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":"Linking machine learning and biophysical structural features in drug discovery.","authors":"Armin Ahmadi, Shivangi Gupta, Vineetha Menon, Jerome Baudry","doi":"10.3389/fmolb.2024.1305272","DOIUrl":"10.3389/fmolb.2024.1305272","url":null,"abstract":"<p><strong>Introduction: </strong>Machine learning methods were applied to analyze pharmacophore features derived from four protein-binding sites, aiming to identify key features associated with ligand-specific protein conformations.</p><p><strong>Methods: </strong>Using molecular dynamics simulations, we generated an ensemble of protein conformations to capture the dynamic nature of their binding sites. By leveraging pharmacophore descriptors, the AI/ML framework prioritized features uniquely associated with ligand-selected conformations, enabling a mechanism-driven understanding of binding interactions. This novel approach integrates biophysical insights with machine learning, focusing on pharmacophoric properties such as charge, hydrogen bonding, hydrophobicity, and aromaticity.</p><p><strong>Results: </strong>Results showed significant enrichment of true positive ligands-improving database enrichment by up to 54-fold compared to random selection-demonstrating the robustness of this approach across diverse proteins.</p><p><strong>Conclusion: </strong>Unlike conventional structure-based or ligand-based screening methods, this work emphasizes the role of specific protein conformations in driving ligand binding, making the process highly interpretable and actionable for drug discovery. The key innovation lies in identifying pharmacophore features tied to conformations selected by ligands, offering a predictive framework for optimizing drug candidates. This study illustrates the potential of combining ML and pharmacophoric analysis to develop intuitive and mechanism-driven tools for lead optimization and rational drug design.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"11 ","pages":"1305272"},"PeriodicalIF":3.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364273","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":"Aqueous humor metabolomic profiling identifies a distinct signature in pseudoexfoliation syndrome.","authors":"Arturs Zemitis, Juris Vanags, Theresa Schiemer, Kristaps Klavins, Guna Laganovska","doi":"10.3389/fmolb.2024.1487115","DOIUrl":"10.3389/fmolb.2024.1487115","url":null,"abstract":"<p><strong>Purpose: </strong>PEXS was first described in 1917, yet its etiology still needs clarification. An imbalance between oxidants and antioxidants plays a significant role. PEXS leads to various ocular complications, including increased risk during cataract surgery due to weak zonules, lens dislocation, and reduced visual outcomes. Our study investigates whether metabolomics can provide insights into this ocular pathology.</p><p><strong>Methods: </strong>The study included 183 patients undergoing cataract surgery at Pauls Stradins Clinical University Hospital. 104 patients did not have PEXS, while 79 were diagnosed with the condition. Intraocular fluid samples from these patients were analyzed using targeted metabolite analysis, performed through HILIC liquid chromatography coupled with mass spectrometry detection.</p><p><strong>Results: </strong>The aqueous humor of PEXS patients contains statistically significant higher levels of cystine (<i>p</i> < 0.001), citrulline (<i>p</i> < 0.001), phenylalanine (<i>p</i> = 0.041), tyrosine (<i>p</i> = 0.025), serine (<i>p</i> = 0.030), arginine (<i>p</i> = 0.017), lactic acid (<i>p</i> = 0.055), tryptophan (<i>p</i> = 0.055), and creatinine (<i>p</i> = 0.022). These results suggest a potential link to ferroptosis.</p><p><strong>Conclusion: </strong>Ferroptosis is a form of programmed cell death characterized by iron-dependent LPO. The inhibition of the antiporter system X_c ^- leads to increased oxidative stress, suggesting that the changes seen in PEXS could be linked to ferroptosis. Our findings indicate that cysteine synthesis occurs via the transsulfation pathway, attributable to inhibiting the antiporter system X_c ^-. Treatment of pseudoexfoliation should lower the oxidative stress inside the anterior chamber by reducing the uptake of PUFAs, lower iron levels, and cysteine supplementation.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"11 ","pages":"1487115"},"PeriodicalIF":3.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364270","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":"Retraction: ZFP36 binds with PRC1 to inhibit tumor growth and increase 5-Fu chemosensitivity of hepatocellular carcinoma.","authors":"","doi":"10.3389/fmolb.2025.1561889","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1561889","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.3389/fmolb.2020.00126.].</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1561889"},"PeriodicalIF":3.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11799729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364274","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":"Elevated expression of <i>ANTXR1</i> gene in tumors is a poor prognostic biomarker for patients with bladder cancer.","authors":"L S Franco, S Arunachalam, A Chauhan, S A Kareff, P L Hallenbeck","doi":"10.3389/fmolb.2024.1520223","DOIUrl":"10.3389/fmolb.2024.1520223","url":null,"abstract":"<p><p>The TEM8 protein coded by the <i>ANTXR1</i> gene represents an emerging biomarker in solid tumors. In addition to the various roles TEM8 plays in oncogenesis, including angiogenesis, epithelial-to-mesenchymal transition, and cell migration, it has also been shown that the overexpression of the <i>ANTXR1</i> gene in solid tumors correlates with poor prognostic indicators in several solid tumor histologies. As such, TEM8 has been identified as the target of novel oncologic therapies. It is especially attractive given its selective expression on the surface of solid tumor cells and associated stromal cells, such as cancer stem cells, invasive cancer cells, and immune cells, such as macrophages, angiogenic endothelial cells, pericytes, and cancer-associated fibroblasts. Furthermore, TEM8 plays this unique role as a mostly non-mutated gene in solid cancers. Here, we demonstrate that elevated expression of ANTXR1 in bladder cancer showed a statistical difference not only in overall survival (OS) but in progression-free survival (PFS), confirming the prognostic biomarker power of <i>ANTXR1</i> expression.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"11 ","pages":"1520223"},"PeriodicalIF":3.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11798775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364272","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":"Diagnostic potential of CDK1 and STAT1 in acute kidney injury associated with gastrointestinal cancers: a bioinformatics-based study.","authors":"Qiuwan Wei, Yiqing Shen, Yiren Tian, Yunzhi Ling","doi":"10.3389/fmolb.2025.1522246","DOIUrl":"10.3389/fmolb.2025.1522246","url":null,"abstract":"<p><strong>Introduction: </strong>Patients with gastrointestinal cancers are prone to acute kidney injury (AKI) due to treatment or disease progression, and current diagnostic methods exhibit insufficient sensitivity and specificity. This study aims to evaluate the potential value of CDK1 and STAT1 in the diagnosis of AKI in this patient population.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on adjacent tissue, cancerous and the clinical data tissue from 150 gastrointestinal cancer patients treated at our hospital from May 2022 to May 2023. Differentially expressed genes (DEGs) associated with gastrointestinal cancer and kidney injury were identified through bioinformatics analysis. The expression of DEGs proteins in cancerous and adjacent tissues was assessed using immunohistochemical scoring (H scores). Patients were classified into AKI (n = 42) and non-AKI groups (n = 108) according to KDIGO AKI criteria. Univariate and multivariate logistic regression analyses were performed to investigate the influencing factors of AKI occurrence. Spearman correlation analysis was used to explore the relationship between DEGs and AKI biomarkers (Scr, BUN, MAU, and UA). The application value of DEGs in early diagnosis of AKI was evaluated using ROC curves.</p><p><strong>Results: </strong>Bioinformatics analysis identified CDK1, STAT1, COL1A2, and COL1A1 as DEGs related to AKI in gastrointestinal cancer. Immunohistochemical analysis revealed elevated H scores for CDK1, STAT1, COL1A2, and COL1A1 in tumor tissues. Univariate analysis showed no significant differences in age, sex, marital status, education level, monthly income, disease type, cancer stage, or tumor markers (CEA, CA242, CA50) between AKI and non-AKI groups (P > 0.05). However, the AKI group exhibited significantly higher levels of MAU, UA, and H scores for CDK1, STAT1, COL1A2, and COL1A1 compared to the non-AKI group (P < 0.05). Multivariate logistic regression confirmed that MAU, UA, CDK1, and STAT1 are independent risk factors for AKI in gastrointestinal cancer patients. Correlation analysis indicated a significant positive association between CDK1, STAT1, and AKI biomarker levels (P < 0.05). ROC curve analysis demonstrated that CDK1 and STAT1 possess high diagnostic value for early detection of AKI in patients with gastrointestinal cancer, with enhanced efficacy when used in combination.</p><p><strong>Conclusion: </strong>CDK1 and STAT1 serve as early diagnostic indicators for the occurrence of AKI in gastrointestinal cancer patients.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1522246"},"PeriodicalIF":3.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255127","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":"Melanoma-derived cytokines and extracellular vesicles are interlinked with macrophage immunosuppression.","authors":"Shankar Suman, Wendy K Nevala, Alexey A Leontovich, James W Jakub, Liyi Geng, Sarah A McLaughlin, Svetomir N Markovic","doi":"10.3389/fmolb.2024.1522717","DOIUrl":"10.3389/fmolb.2024.1522717","url":null,"abstract":"<p><p>Cytokines play a crucial role in mediating cell communication within the tumor microenvironment (TME). Tumor-associated macrophages are particularly influential in the regulation of immunosuppressive cytokines, thereby supporting tumor metastasis. The upregulation of Th2 cytokines in cancer cells is recognized for its involvement in suppressing anticancer immunity. However, the association between these cytokines and tumor-secreted extracellular vesicles (EVs) remains poorly understood. Therefore, our objective was to investigate the connection between tumor-promoting macrophages and melanoma-derived EVs. The analysis from altered cytokine profile data showed that melanoma-derived EVs upregulate Th2 cytokine expression in naïve macrophages, thereby contributing to the promotion of tumor-supporting functions. Notably, many of these cytokines were also found to be upregulated in metastatic melanoma patients (n = 30) compared to healthy controls (n = 33). Overall, our findings suggest a strong connection between melanoma secretory EVs and the induction of tumor-associated macrophages that facilitates the development of an immunosuppressive TME, supporting melanoma metastasis through regulation at both local and systemic levels.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"11 ","pages":"1522717"},"PeriodicalIF":3.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255097","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":"Labeling tumor-associated extracellular vesicles with antibody-DNA conjugates for quantitative analysis.","authors":"Xiao Du, Hongxiu Li, Shiyi Shen, Chao Tian, Xiaohuan Cao, Xingang Xu, Nan Xu, Shuling Wang, Qingchang Tian","doi":"10.3389/fmolb.2025.1531108","DOIUrl":"10.3389/fmolb.2025.1531108","url":null,"abstract":"<p><strong>Introduction: </strong>Extracellular vesicles (EVs) shed from tumor cells into peripheral circulation or other body fluids are promising biomarkers for cancer diagnosis with enormously long circulation. Consequently, precise methods for differentiating normal and tumor-associated EVs (TAEs) are required.</p><p><strong>Methods: </strong>This study used quantifiable antibody-DNA conjugate-assisted quantitative methods combined with proximity ligation technology to detect TAEs. The antibody-DNA conjugate contained one antibody associated with three oligonucleotides for signal amplification. The antibody in the conjugate can recognize the surface tumor antigens of TAEs. Simultaneously, DNA in the conjugate is attached to the surfaces of TAEs and holds the signal amplification post, converting protein identities to DNA amplification for protein detection, even at the molecular level.</p><p><strong>Results: </strong>These findings revealed that TAEs can be quantitatively detected using DNA-mediated quantitative polymerase chain reaction (qPCR). Antibody-DNA conjugates were used to recognize the epithelial cell adhesion molecule (EpCAM) antigen on the TAE surface and quantify the antigen using qPCR for cancer analysis.</p><p><strong>Discussion: </strong>This method proposed a new quantitative detection approach for TAEs, which aim to identify specific EV-associated markers for diagnostic or therapeutic, this method could inspire a new idea for tumor diagnosis and detection of other diseases.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1531108"},"PeriodicalIF":3.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255147","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":"Detection of fusion events by RNA sequencing in FFPE versus freshly frozen colorectal cancer tissue samples.","authors":"Maxim Sorokin, Vladimir Lyadov, Maria Suntsova, Marat Garipov, Anna Semenova, Natalia Popova, Egor Guguchkin, Rustam Heydarov, Marianna Zolotovskaia, Xiaowen Zhao, Qing Yan, Ye Wang, Evgeny Karpulevich, Anton Buzdin","doi":"10.3389/fmolb.2024.1448792","DOIUrl":"10.3389/fmolb.2024.1448792","url":null,"abstract":"<p><p>Gene fusion events result in chimeric proteins that are frequently found in human cancers. Specific targeted therapies are available for several types of cancer fusions including receptor tyrosine kinase gene moieties. RNA sequencing (RNAseq) can directly be used for detection of gene rearrangements in a single test, along with multiple additional biomarkers. However, tumor biosamples are usually formalin-fixed paraffin-embedded (FFPE) tissue blocks where RNA is heavily degraded, which in theory may result in decreased efficiency of fusion detection. Here, for the first time, we compared the efficacy of gene fusion detection by RNAseq for matched pairs of freshly frozen in RNA stabilizing solution (FF) and FFPE tumor tissue samples obtained from 29 human colorectal cancer patients. We detected no statistically significant difference in the number of chimeric transcripts in FFPE and FF RNAseq profiles. The known fusion <i>KANSL1-ARL17A/B</i> occurred with a high frequency in 69% of the patients. We also detected 93 new fusion genes not mentioned in the literature or listed in the ChimerSeq database. Among them, 11 were found in two or more patients, suggesting their potential role in carcinogenesis. Most of the fusions detected most probably represented read-through, microdeletion or local duplication events. Finally, in one patient, we detected a potentially clinically actionable in-frame fusion of <i>LRRFIP2</i> and <i>ALK</i> genes not previously described in colorectal cancer with an intact tyrosine kinase domain that can be potentially targeted by ALK inhibitors.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"11 ","pages":"1448792"},"PeriodicalIF":3.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188691","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":"Editorial: Oncolytic virotherapy, volume II.","authors":"Ahmed Majeed Al-Shammari, Pier Paolo Piccaluga","doi":"10.3389/fmolb.2025.1552643","DOIUrl":"10.3389/fmolb.2025.1552643","url":null,"abstract":"","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1552643"},"PeriodicalIF":3.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188693","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}