Biomolecules最新文献

{"title":"Adaptation to Arginine Deprivation Leads to a More Aggressive, Therapy-Resistant Phenotype in HNSCC Cells.","authors":"Oleg Chen, Olena Vovk, Nikita Polishchuk, Oksana Mayevska, Galyna Shuvayeva, Melike Demir, Vasyl Lukiyanchuk, Leoni A Kunz-Schughart, Anna Dubrovska, Oleh Stasyk","doi":"10.3390/biom15060900","DOIUrl":"10.3390/biom15060900","url":null,"abstract":"<p><p><i>Purpose:</i> The development of acquired resistance to arginine deprivation therapy (ADT) is a major barrier to its efficacy. This study aimed to elucidate the possible mechanisms underlying the resistance to ADT. <i>Methods:</i> We applied repeated ADT and established a subline SAS-R9 of the human head and neck squamous cell carcinoma (HNSCC) cells semi-resistant to arginine (Arg) deprivation <i>in vitro</i>. This subline was compared to the parental SAS cell lines for its relative clonogenic proliferation, aggregation, adhesion, and migration capacities. The transcriptomic changes were assessed by RNA sequencing. Signaling pathway alterations were confirmed by RT-PCR and Western blotting. Relative cell radioresistance was analyzed by radiobiological clonogenic survival assay. DNA double-strand break (DSB) repair was assessed by γH2A.X foci analysis. <i>Results:</i> SAS-R9 cells showed higher survival in response to ADT and radiotherapy, elevated clonogenic proliferation rate, cell-cell aggregation, and cell-matrix adhesion, along with increased epithelial-mesenchymal transition (EMT) markers and enhanced DNA DSB repair, potentially related to a more aggressive and therapy-resistant phenotype. <i>Conclusions:</i> While acute ADT has radiosensitizing potential, this new study suggests that long-term, repeated ADT is associated with cell selection and reprogramming, resulting in resistance to radiotherapy-induced DNA damage and higher tumor cell aggressiveness.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494318","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":"Ankyrin-G and Its Binding Partners in Neurons: Orchestrating the Molecular Structure of the Axon Initial Segment.","authors":"Xiaowei Zhu, Yanyan Yu, Zhuqian Jiang, Yoshinori Otani, Masashi Fujitani","doi":"10.3390/biom15060901","DOIUrl":"10.3390/biom15060901","url":null,"abstract":"<p><p>The axon initial segment (AIS) is a specialized subcellular domain that plays an essential role in action potential initiation and the diffusion barrier. A key organizer of the AIS is Ankyrin-G, a scaffolding protein responsible for clustering voltage-gated ion channels, cell adhesion molecules (CAMs), and cytoskeletal components at this critical neuronal domain. Recent proteomic analyses have revealed a complex network of proteins in the AIS, emphasizing Ankyrin-G's central role in its molecular architecture. This review discusses new findings in the study of AIS-associated proteins. It explains how Ankyrin-G and its binding partners (such as ion channels, CAMs, spectrins, actin, and microtubule-associated proteins including end-binding protein 3, tripartite motif-containing protein 46, and calmodulin-regulated spectrin-associated protein 2) organize their structure. Understanding the dynamic regulation and molecular interactions within the AIS offers insights into neuronal excitability and reveals potential therapeutic targets for axonal dysfunction-related diseases. Through these dynamic interactions, Ankyrin-G ensures the proper alignment and dense clustering of key channel complexes, thereby maintaining the AIS's distinctive molecular and functional identity. By further unraveling the complexity of Ankyrin-G's interactome, our understanding of AIS formation, maintenance, and plasticity will be considerably enhanced, contributing to the elucidation of the pathogenesis of neurological and neuropsychiatric disorders.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494336","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":"Cycloadditions as a Sweet Route to 'Double <i>C</i>-Glycosylation'.","authors":"Kevin P P Mahoney, Rosemary Lynch, Rhea T Bown, Sunil V Sharma, Piyasiri Chueakwon, G Richard Stephenson, David B Cordes, Alexandra M Z Slawin, Rebecca J M Goss","doi":"10.3390/biom15060905","DOIUrl":"10.3390/biom15060905","url":null,"abstract":"<p><p>Pharmaceuticals, such as the antibiotic erythromycin, and sodium-dependent glucose transporter (SGLT1 & SGTL2) inhibitors such as Bexagliflozin (diabetes) and Sotagliflozin (heart disease), are often sugar-decorated (glycosylated). Glycosylation is a key component of the binding motif in SGLT inhibitors and, in natural products, glycosylation often confers improved bioactivity and bioavailability. Whilst a single <i>C</i>-glycoside link between a sugar moiety and its aglycone core is a common feature in natural products isolated to date, only a small number, including the antibiotics granaticin and sarubicin, are covalently bonded twice to a single sugar moiety. The way in which this \"double <i>C</i>-glycosylation\" is naturally mediated is not yet known, yet has been speculated on. Here, we report the exploration and development of a potentially biomimetic procedure that utilises intermolecular cycloaddition chemistry to access new \"double <i>C</i>-glycosylated\" products and enables the creation of bridged polycyclic ethers from a common maltol-derived oxidopyrylium salt precursor.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494399","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":"Advances in Local Drug Delivery for Periodontal Treatment: Present Strategies and Future Directions.","authors":"Mayuka Nakajima, Mayuko Yanagawa, Honoka Takikawa, Truong Tran Thien, Lorena Zegarra-Caceres, Chunyang Yan, Koichi Tabeta","doi":"10.3390/biom15060903","DOIUrl":"10.3390/biom15060903","url":null,"abstract":"<p><p>Periodontitis is a highly prevalent, irreversible inflammatory disease characterized by the destruction of tooth-supporting tissues, eventually leading to tooth loss. Conventional treatment involves the mechanical removal of the subgingival biofilm, which is a major cause of gingival inflammation. However, the inaccessibility of deep-seated polymicrobial biofilms limits its effectiveness. Despite the adjunct use of systemic antimicrobials, their low site-specific bioavailability and systemic side effects remain concerns. Local drug administration offers a targeted alternative. However, the dynamic oral environment, which is characterized by continuous salivary and gingival crevicular fluid flow, poses challenges in maintaining therapeutic drug levels. Drug delivery systems (DDSs) provide technical solutions to overcome these limitations. With advancements in materials science and nanotechnology, diverse local DDS (LDDS) formulations tailored for periodontal applications have been developed. While traditionally focused on infection control, the application of LDDSs has expanded beyond antimicrobial therapy. Increasing attention has been paid to LDDS-based regenerative strategies, which aim to overcome the limitations of conventional regenerative therapies. This review aims to provide a comprehensive overview of the current and emerging DDS strategies in periodontal therapy, focusing on their applications in infection management and bone regeneration and discussing their limitations and prospects for clinical translation.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494320","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":"Gene Fusions as Potential Therapeutic Targets in Soft Tissue Sarcomas.","authors":"Qiongdan Zheng, Tong Wang, Zijian Zou, Wenjie Ma, Zirui Dong, Jingqin Zhong, Wanlin Liu, Yu Xu, Tu Hu, Wei Sun, Yong Chen","doi":"10.3390/biom15060904","DOIUrl":"10.3390/biom15060904","url":null,"abstract":"<p><p>Though having been discovered in one third of sarcomas, gene fusions are less studied in their roles as potential therapeutic targets, making conventional modalities the mainstream treatment options for sarcoma patients. Recent decades have witnessed encouraging progress in basic research delving into mechanisms underlying how gene fusions drive sarcomas; nevertheless, further translation to clinical application fails to keep abreast with the advances achieved in basic science. In this review, we will focus on key chromosomal translocation-driven sarcomas defined by characteristic hallmark fusion oncoproteins, including Ewing sarcoma with EWSR1-FLI1/ERG fusion, epithelioid hemangioendothelioma with WWTR1-CAMTA1/YAP1-TFE1 fusion, and others, to discuss the potential of directly targeting these fusion proteins as therapeutic targets in preclinical and clinical contexts.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191211/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494424","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-1α: A Key Factor Mediating Tumor Cells from Digestive System to Evade NK Cell Killing via Activating Metalloproteinases to Hydrolyze MICA/B.","authors":"Quan Zhu, Shuyi Tang, Ting Huang, Chunjing Chen, Biyuan Liu, Chuyu Xiao, Liugu Chen, Wang Wang, Fangguo Lu","doi":"10.3390/biom15060899","DOIUrl":"10.3390/biom15060899","url":null,"abstract":"<p><p>Malignant tumors of the digestive system are widespread and pose a serious threat to humans. Immune escape is an important factor promoting the deterioration of malignant tumors in the digestive system. Natural killer cells (NK cells) are key members of the anti-tumor and immune surveillance system, mainly exerting cytotoxic effects by binding to the activating receptor natural killer cell group 2D (NKG2D) on their cell surface with the corresponding ligands (major histocompatibility complex class I chain-related protein A/B, MICA/B) on the surface of tumor cells. Malignant tumors of epithelial origin usually highly express NKG2D ligands such as MICA, which can attract NK cells to kill tumor cells and also serve as an important basis for NK cell-based immunotherapy. Tumor cells highly express hypoxia-inducible factor-1α (HIF-1α), which promotes the expression of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs). These metalloproteinases hydrolyze MICA and other ligands on the surface of tumor cells to generate soluble molecules. These soluble ligands, when binding to NKG2D, cannot activate NK cells and also block the binding of NKG2D to MICA on the surface of tumor cells, enabling tumor cells to evade the killing effect of NK cells. Almost all organs in the digestive system originate from epithelial tissue, so the soluble ligands generated by the HIF-1α/MMPs or HIF-1α/ADAMs signaling pathways play a crucial role in evading NK cell killing. A comprehensive understanding of this immune escape process is helpful for a deeper understanding of the molecular mechanism of NK cell anti-tumor activity. This article reviews the molecular mechanisms of common digestive system malignancies evading NK cell killing, providing new insights into the mechanism of tumor immune escape.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494428","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":"Enhanced Therapeutic Efficacy of Omeprazole Nanosuspension in Ethanol-Induced Gastric Ulcer: A Focus on Oxidative Stress and Inflammatory Pathways.","authors":"Mody Albalawi, Sahar Khateeb","doi":"10.3390/biom15060902","DOIUrl":"10.3390/biom15060902","url":null,"abstract":"<p><p>Gastric ulcer is a concerning condition that affects numerous individuals globally. Omeprazole (OMP), a well-known drug for treating stomach ulcers, has been associated with several adverse effects and limited solubility. The study aimed to create an omeprazole nanosuspension (OMP-NS) with improved solubility and bioavailability. Additionally, the study investigated the potential therapeutic effects of OMP-NS on ethanol-induced gastric injury in rats, comparing it to traditional OMP therapy to identify novel therapeutic alternatives. The characterization of the OMP-NS was assessed using DLS, TEM, XRD, FTIR, UV spectrophotometric analysis, in vitro release studies, and entrapment efficiency (EE) assays. A total of 24 male Wistar albino rats (weighing 150-200 g, aged 8-10 weeks) were randomly divided into four groups (six rats/group). Gastric injury was induced using absolute ethanol (5 mL/kg), followed by oral administration of either OMP or OMP-NS (20 mg/kg) for 7 days. Data were analyzed using one-way ANOVA accompanied by the Bonferroni post hoc test or the Kruskal-Wallis test, based on data distribution, with significance set at <i>p</i> < 0.05. The OMP-NS demonstrated a Z-average diameter of 216.1 nm, a polydispersity index of 0.2, and a zeta potential of -19.6 mV. The particles were predominantly spherical with an average size of 67.28 nm. In vitro release studies showed 97.78% release at 8 h, with an EE% of 96.97%. Ethanol-induced gastric ulcers were associated with oxidative stress, characterized by elevated levels of NADPH, ROS, MDA, and NO, while the level of SOD was reduced. It was accompanied by increased inflammatory markers HMGB1, which subsequently increased TLR-2, MyD88, NF-κBp56, NLRP3, TNF-α, IL-1β, and IL-6 levels; conversely, a significant decrease in Nrf2/PPAR-γ/SIRT1 levels was observed. In contrast, OMP-NS administration significantly reduced oxidative stress and inflammatory markers, restored SOD activity, and upregulated protective pathways Nrf2/PPAR-γ/SIRT1 more effectively than conventional OMP therapy. In conclusion, OMP-NS represents a promising therapeutic strategy with notable anti-inflammatory and anti-ulcerogenic effects in ethanol-induced gastric ulcers.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494413","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":"A Novel Copper Ionophore Nanoshuttle (Winged Cu) for Inducing Cuproptosis in B16 Melanoma Cells.","authors":"Yuhuan Wu, Ziyao Chang, Wenhao Wang, Chuanbin Wu, Xin Pan, Zhengwei Huang","doi":"10.3390/biom15060895","DOIUrl":"10.3390/biom15060895","url":null,"abstract":"<p><p>Cuproptosis, a newly discovered copper-dependent programmed cell death pathway, represents a promising approach for anticancer therapy. However, the efficacy of cuproptosis critically depends on intracellular copper accumulation. Traditional copper ionophores have limited therapeutic efficacy due to their reliance on serum copper levels. Therefore, the development of novel copper ionophores to enhance intracellular copper levels is urgently needed. In this study, we targeted a melanoma model and pioneered the application of Bis(2-hydroxyethyl)dithiocarbamic acid copper(II) [Cu(HEDTC)₂] as a highly efficient copper ionophore for inducing cuproptosis in B16 melanoma cells. Compared to conventional copper ionophores, Cu(HEDTC)₂ exhibits superior intracellular copper delivery efficiency, thereby enhancing the induction of cuproptosis. We further constructed a Cu(HEDTC)₂@Soluplus-nanomicelle (CS NM) system designed to disrupt copper ion homeostasis in tumor cells and amplify cuproptosis. In this system, Cu(HEDTC)₂, as a novel copper ionophore, significantly enhanced the copper level in B16 melanoma cells. Upon cellular internalization, CS NM underwent degradation and released copper ions, which subsequently triggered cuproptosis by causing abnormal aggregation of mitochondrial lipoylated proteins. This study provides a new experimental foundation and potential therapeutic strategy for cuproptosis-based cancer treatment.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494316","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":"Exercise-Mediated Skeletal Muscle-Derived IL-6 Regulates Bone Metabolism: A New Perspective on Muscle-Bone Crosstalk.","authors":"Chenyu Zhu, Xiaoqing Ding, Min Chen, Jie Feng, Jun Zou, Lingli Zhang","doi":"10.3390/biom15060893","DOIUrl":"10.3390/biom15060893","url":null,"abstract":"<p><p>Skeletal muscles and bones maintain musculoskeletal system function through their collaborative interaction, whereby muscles regulate bone metabolism via mechanical coupling. An increasing number of studies have shown that various cytokines secreted by skeletal muscles during exercise closely regulate the balance of bone homeostasis. Interleukin-6 (IL-6), one of the first muscle-secreted factors to be discovered, not only plays an important role in regulating the function of the muscle itself but also regulates bone metabolic processes in a bidirectional manner through multiple complex signal transduction pathways, thereby affecting the balance between bone formation and bone resorption. The exact mechanism by which IL-6 regulates bone metabolism is not fully understood, and there are few summaries on how exercise affects bone metabolism through IL-6 from skeletal muscles. Accordingly, this study will take skeletal muscle-derived IL-6 as an entry point to explore how the cross-organ regulatory activities of the muscles targeting bones during exercise affect bone metabolic processes. This study also aims to improve the mechanism of muscle-bone crosstalk under the effect of exercise and provide a theoretical basis and clinical diagnosis and treatment ideas from multiple perspectives for exercise to improve bone health.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494417","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":"Signal Peptides: From Molecular Mechanisms to Applications in Protein and Vaccine Engineering.","authors":"Shuai Zhang, Zhihui He, Hui Wang, Jingbo Zhai","doi":"10.3390/biom15060897","DOIUrl":"10.3390/biom15060897","url":null,"abstract":"<p><p>Signal peptides (SPs) are short amino acid sequences located at the N-terminus of nascent proteins and are widely present across various life forms. They play crucial roles in protein synthesis, transmembrane transport, and intracellular signal transduction. With the rapid advancement of bioinformatics, studies have revealed that the functions of SPs are far more complex than previously understood. In recombinant protein expression systems, the rational design and optimization of SPs are essential for enhancing the expression efficiency and secretion level of exogenous proteins. Meanwhile, the application value of SPs in vaccine development has attracted increasing attention. This review summarizes the structural characteristics, functional mechanisms, and applications of SPs in recombinant protein production and SP-based vaccines. It also discusses their biological roles, the significance of engineering optimization strategies, and the current challenges, aiming to provide theoretical support and practical guidance for improving recombinant protein yield and advancing SP-based vaccine development.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 6","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494478","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}