TheranosticsPub Date : 2025-07-25eCollection Date: 2025-01-01DOI: 10.7150/thno.113059
Vladimir R Cherkasov, Elizaveta N Mochalova, Andrey V Babenyshev, Maxim P Nikitin
{"title":"All-in-one Biocomputing Nanoagents with Multilayered Transformable Architecture based on DNA Interfaces.","authors":"Vladimir R Cherkasov, Elizaveta N Mochalova, Andrey V Babenyshev, Maxim P Nikitin","doi":"10.7150/thno.113059","DOIUrl":"https://doi.org/10.7150/thno.113059","url":null,"abstract":"<p><p>The pathogen diversity to infiltrate the host organism highlights the demand for equally sophisticated mechanisms for their prevention. The development of \"intelligent\" agents with molecular logic capabilities are of great hope, but their full theranostic potential has yet to be realized. <b>Methods:</b> The original concept of nanoagents based on \"Biocomputing based on particle disassembly\" technology has been extended to nucleic acids (NAs) interfaces and inputs. By exploiting the unique properties of NAs, we designed nanostructures that can implement all basic single- and dual-input logic gates on a unified nanoparticle platform through DNA strand displacement triggered by oligonucleotide inputs. Performance of nanostructures was investigated across various output signal detection formats including specific interaction with nanosized objects and targeting cells. <b>Results:</b> Here, we demonstrate autonomous theranostic biocomputing agents based on nanoparticles and DNA interfaces (\"DNA-transformers\") capable of executing a functionally complete set of Boolean logic gates (YES, NOT, AND, and OR) within a single all-in-one particle structure. Each DNA-transformer is constructed through a multi-layered self-assembly of nanoparticles via DNA-interfaces. The route of the agent's disassembly induced by the particular combination of the specific ssDNA inputs determines the agents' ability to produce the programmed outputs compatible with theranostic applications such as specific targeting of HER2/neu-positive cancer cells. <b>Conclusions:</b> The developed all-in-one DNA-based nanoagents represent a significant advancement in molecular logic devices, establishing a versatile platform for smart nanoagents equally suitable for diagnostic and therapeutic applications.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8451-8472"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Inhibitory leukocyte immunoglobulin-like receptors, subfamily B (LILRBs) in human diseases: structure, roles, mechanisms, and clinical applications.","authors":"Yuxiu Zhang, Yuanyuan Xu, Qihui Wu, Xiaodan Fu, Yimin Li, Anqi Li","doi":"10.7150/thno.116951","DOIUrl":"https://doi.org/10.7150/thno.116951","url":null,"abstract":"<p><p>Leukocyte immunoglobulin-like receptors, subfamily B (LILRBs), are a class of critical immunosuppressive receptors that contribute to immune homeostasis by transmitting suppressive signals upon binding to ligands such as major histocompatibility complex class I molecules. They play key roles in modulating both innate and adaptive immune responses. This review summarizes the structural features, ligand interactions, signaling pathways, and expression regulation of LILRBs, and discusses their roles in immune cell function and disease progression, particularly in the tumor microenvironment. We also review current progress in the development of LILRB-targeted therapies for hematological malignancies and solid tumors and outline the challenges and future directions in translating these findings into clinical applications. By integrating recent advances, this review provides a framework for understanding the potential of LILRBs as therapeutic targets in cancer and immune-related disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8222-8258"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144969860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Engineered nanovesicle platform simultaneously triggers YAP-dependent ferroptosis and reprograms T-cell immunity through miR-150-3p codelivery in melanoma microenvironment.","authors":"Jiemin Wang, Zhenguo Zhao, Haopeng Yang, Ruixuan Wang, Shu Wang, Jiale Yu, Yujia Wang, Ruihua Liu, Yani Chen, Yueshi Liu, Kesong Shi, Pengyong Han, Miao Liu, Jing Miao, Xiaoyang Li, Xiangnan Li, Haiquan Yu","doi":"10.7150/thno.115860","DOIUrl":"https://doi.org/10.7150/thno.115860","url":null,"abstract":"<p><p><b>Rationale:</b> Melanoma remains a highly aggressive malignancy with limited effective therapies and frequent resistance to immune checkpoint blockade (ICB). Extracellular vesicles (EVs) represent a promising platform for RNA-based therapeutics, but their clinical translation is impeded by inefficient cargo loading and insufficient tumor-specific targeting. To address these limitations, we developed an engineered EV strategy integrating efficient miRNA packaging with tumor-targeting surface modifications to enhance therapeutic outcomes in melanoma. <b>Methods:</b> Engineered EVs (iEV-150) were generated by co-expressing miR-150-3p and Annexin A2 (ANXA2) in HEK293T cells, followed by surface modification with tumor-targeting iRGD peptides. Mechanistic insights were obtained using RNA sequencing, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays. Ferroptosis induction was evaluated through lipid peroxidation analysis, mitochondrial membrane potential assays, and transmission electron microscopy (TEM). Therapeutic efficacy and biodistribution were assessed <i>in vivo</i> using subcutaneous and metastatic melanoma mouse models. Immune modulation was examined by analyzing CD8⁺ T cell activation via flow cytometry in co-cultures of patient-derived CD8⁺ T cells and melanoma cells treated with iEV-150. <b>Results:</b> miR-150-3p was elevated in melanoma-derived EVs, and ANXA2 was identified as a key RNA-binding protein that selectively facilitated its loading into EVs. iEV-150 exhibited enhanced uptake by melanoma cells and improved tumor-specific accumulation <i>in vivo</i>. Mechanistically, iEV-150 suppressed NF2 expression, disrupted the NF2-LATS1 interaction, activated YAP signaling, and subsequently upregulated ferroptosis-related genes ACSL4 and CHAC1, thereby inducing ferroptosis through the NF2-Hippo-YAP axis. In addition to its direct anti-tumor effects, iEV-150 promoted CD8⁺ T cell infiltration and activation within the tumor microenvironment, and significantly enhanced the therapeutic efficacy of ICB in melanoma models. <b>Conclusions:</b> iEV-150 integrates ANXA2-mediated miRNA loading, tumor-specific targeting, ferroptosis induction, and immune microenvironment reprogramming. This engineered EV strategy provides an effective RNA-based therapeutic platform to overcome ICB resistance and enhance precision treatment in melanoma.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8377-8403"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TheranosticsPub Date : 2025-07-25eCollection Date: 2025-01-01DOI: 10.7150/thno.112209
Zhuang Chen, Zuo Yang, Zhiping Rao, Yi Luo, Weijing Liu, Chaoqiang Qiao, Qian Jia, Peng Yang, Ruili Zhang, Zhongliang Wang
{"title":"A pyroptosis proportion tunable nano-modulator for cancer immunotherapy.","authors":"Zhuang Chen, Zuo Yang, Zhiping Rao, Yi Luo, Weijing Liu, Chaoqiang Qiao, Qian Jia, Peng Yang, Ruili Zhang, Zhongliang Wang","doi":"10.7150/thno.112209","DOIUrl":"https://doi.org/10.7150/thno.112209","url":null,"abstract":"<p><p><b>Rationale:</b> Pyroptosis, a form of programmed cell death mediated by gasdermin proteins, holds significant potential in cancer immunotherapy. However, precise control of pyroptosis in cancer cells is essential to avoid biosafety concerns. This study aimed to develop a tumor-targeted and tunable pyroptosis-inducing strategy to enhance antitumor efficacy while minimizing systemic side effects. <b>Methods:</b> An innovative H<sub>2</sub>S-activated nanomodulator equipped with an optical switch was designed for tumor-specific and adjustable pyroptosis induction. The nanomodulator was activated by H<sub>2</sub>S in the tumor microenvironment of colorectal cancer and further regulated by laser irradiation. Gasdermin-E-mediated pyroptosis was triggered through the synergistic effects of photothermal temperature modulation and demethylation. The proportion of cells undergoing pyroptosis was precisely controlled within a tunable range. <b>Results:</b> The nanomodulator successfully induced pyroptosis in microsatellite-stable colorectal cancer cells within a tunable range of 0-31%. This precise regulation significantly enhanced antitumor efficacy while minimizing systemic side effects. The combination of photothermal modulation and demethylation ensured effective and safe pyroptosis induction. <b>Conclusions:</b> This study presents a novel and precise method for controlling pyroptosis using photothermal temperature modulation. The findings provide essential guidance for in vivo applications and offer valuable insights into the development of nanomedicines capable of safely and effectively inducing adjustable proportion of pyroptosis in cancer therapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8320-8336"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TheranosticsPub Date : 2025-07-25eCollection Date: 2025-01-01DOI: 10.7150/thno.115572
Mengdi Li, Yuting Lin, Jiayu Wang, He Yang, Danhui Ma, Ye Tian, Yi Wang, Liu Yang, Umar Farooq, Yinyin Wang, Fangli Ren, Jian Sheng, Guoqing Zhang, Liang Chen, Jun Li, Xiangnan Li, Zhijie Chang
{"title":"CREPT promotes LUAD progression by enhancing the CDK9 and RNAPII assembly to promote ERK-driven gene transcription.","authors":"Mengdi Li, Yuting Lin, Jiayu Wang, He Yang, Danhui Ma, Ye Tian, Yi Wang, Liu Yang, Umar Farooq, Yinyin Wang, Fangli Ren, Jian Sheng, Guoqing Zhang, Liang Chen, Jun Li, Xiangnan Li, Zhijie Chang","doi":"10.7150/thno.115572","DOIUrl":"https://doi.org/10.7150/thno.115572","url":null,"abstract":"<p><p><b>Background:</b> Despite advancements in EGFR- and KRAS-targeted therapies for lung adenocarcinoma (LUAD), novel targets are needed for patients unresponsive or resistant to current treatments. This study demonstrates the critical role of CREPT in modulating ERK-downstream gene transcription in LUAD progression. <b>Methods:</b> CREPT expression and function were investigated using human LUAD tissues, EGFR/KRAS mutant LUAD cell lines, and mouse models. Micro-CT was used to monitor tumor progression. Adeno-associated virus (AAV)-mediated CREPT depletion was employed as a therapeutic strategy. RNA sequencing and luciferase reporter assays identified differentially expressed genes (DEGs) and affected signaling pathways. Protein interactions and CDK9 occupancy were assessed using multiplex immunofluorescence, immunoprecipitation, and chromatin immunoprecipitation (ChIP). <b>Results:</b> CREPT overexpression correlated with poor LUAD patient survival and enhanced tumorigenesis in EGFR or KRAS mutant LUAD cells. <i>CREPT</i> deletion impaired LUAD initiation and progression in the CC10-rtTA;TetO-<i>KRAS<sup>G12D</sup></i> mouse model. Mechanistically, CREPT promoted CDK9 assembly with RNA polymerase II (RNAPII) following ERK activation, enhancing transcription of malignancy-related genes downstream of KRAS-ERK-Elk-1 signaling. CREPT depletion and the mutants R106A and S134A disrupting CREPT-RNAPII interaction reduced CDK9 occupancy at Elk-1 downstream gene promoters and their expression. Targeting CREPT in both CC10-rtTA;TetO-<i>KRAS<sup>G12D</sup></i> and xenograft mouse models resulted in tumor growth arrest. Furthermore, in a humanized mouse model, AAV-mediated CREPT silencing inhibited tumor progression and showed synergistic potential with pembrolizumab. <b>Conclusion:</b> Our findings highlight CREPT as a pivotal regulator of LUAD progression and suggest it could be a potential therapeutic target for patients with EGFR or KRAS mutations insensitive or resistant to targeted therapies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8337-8359"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TheranosticsPub Date : 2025-07-25eCollection Date: 2025-01-01DOI: 10.7150/thno.117523
Mengyu Li, Yu Wang, Zhiqiang Hu, Shiqian Huang, Pu Chen, Lin Chen, Jing Wu, Zhouyang Wu, Shanglong Yao, Yiyi Yang
{"title":"PTEN-mediated senescence of lung epithelial cells drives ventilator-induced pulmonary fibrosis.","authors":"Mengyu Li, Yu Wang, Zhiqiang Hu, Shiqian Huang, Pu Chen, Lin Chen, Jing Wu, Zhouyang Wu, Shanglong Yao, Yiyi Yang","doi":"10.7150/thno.117523","DOIUrl":"https://doi.org/10.7150/thno.117523","url":null,"abstract":"<p><strong>Rationale: </strong>Mechanical ventilation (MV), a life-saving intervention for acute respiratory distress syndrome (ARDS), may exacerbate pulmonary fibrosis (PF) through unclear mechanisms. Although Phosphatase and Tensin homolog (PTEN) suppresses chronic PF, its role in MV-induced PF remains unknown. This study will determine whether PTEN mediates MV-PF via lung epithelial cell senescence. <b>Methods:</b> Human lung epithelial cells exposed to hydrochloric acid (HCl) and mechanical stretch (48 hours) and a murine \"two-hit\" (HCl+MV) model (14-day observation) were used. PTEN's role was assessed via siRNA (<i>in vitro</i>) and knockout (<i>in vivo</i>). Single-cell transcriptomics analyzed senescence-associated secretory phenotype (SASP) and pathway enrichment. RG7388 (MDM2-P53 inhibitor) was administered to PTEN knockout mice to evaluate P53-mediated senescence. <b>Results:</b> HCl+MV induced epithelial-mesenchymal transition (EMT) and fibrosis <i>in vitro</i> and <i>in vivo</i>. PTEN knockout or knockdown attenuated these effects. Single-cell profiling indicated PTEN's role in EMT and fibrosis via cell senescence pathways, particularly in epithelial cells exhibiting imbalances in the SASP scores. Furthermore, our experiments confirmed that senescence activation during fibrosis was reversed by PTEN inhibition. RG7388 treatment in PTEN knockout mice implicated P53-mediated senescence in PTEN's regulatory role. <b>Conclusions:</b> Our study demonstrates that PTEN plays a pivotal role in MV-PF, by mediating pulmonary epithelial cell senescence. Future studies may focus on developing strategies to modulate PTEN activity and cell senescence to prevent or treat this devastating disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8360-8376"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TheranosticsPub Date : 2025-07-25eCollection Date: 2025-01-01DOI: 10.7150/thno.116153
Shijing Wang, Lei Zhang, Minghao Wang, Xiumei Yin, Xinyao Dong, Xingyu Wu, Weijie Li, Wen Xu, Xiaoyun Mao
{"title":"Engineered upconversion nanoparticles for breast cancer theranostics.","authors":"Shijing Wang, Lei Zhang, Minghao Wang, Xiumei Yin, Xinyao Dong, Xingyu Wu, Weijie Li, Wen Xu, Xiaoyun Mao","doi":"10.7150/thno.116153","DOIUrl":"https://doi.org/10.7150/thno.116153","url":null,"abstract":"<p><p>Breast cancer (BC) remains the most prevalent cancer among women and a leading cause of cancer-related mortality worldwide, posing a significant threat to public health. Rare earth (RE)-doped upconversion nanoparticles (UCNPs) have emerged as a promising nanoplatform for BC management, owing to their exceptional photophysical properties and design flexibility. Unlike conventional fluorescent probes, engineered UCNPs absorb near-infrared (NIR) light, enabling deep tissue penetration while mitigating tissue damage and spontaneous fluorescence interference. Furthermore, through core-shell structure engineering and functionalization, multiple diagnostic and therapeutic modules can be integrated within a single NP, enabling theranostic applications for BC. This review comprehensively summarizes recent advances in engineered UCNPs for BC theranostics. It begins by introducing the luminescence mechanisms, controllable synthesis methods, and surface modification strategies of UCNPs. Next, it explores the fundamental biological effects of UCNPs, including biodistribution, metabolic pathways, and biotoxicity. Subsequently, we systematically review applications of engineered UCNPs in BC molecular imaging, biomarker detection, phototherapy, smart drug/gene delivery, and immunotherapy. Finally, current challenges and clinical translation prospects of UCNPs are discussed.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8259-8319"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144969904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"PTEN restoration and CXCR2 depletion synergistically enhance the effect of enzalutamide and inhibit bone metastatic CRPC.","authors":"Jiyuan Chen, Luyao Gong, Simeng Cao, Guanshan Song, Yeheng Peng, Yuanyuan Wang, Yan-Ru Lou, Teemu J Murtola, Yao Wu, Ganjun Yu, Yuan Gao","doi":"10.7150/thno.114534","DOIUrl":"https://doi.org/10.7150/thno.114534","url":null,"abstract":"<p><p><b>Rationale:</b> Enzalutamide (Enz) is the first-line therapy for castration-resistant prostate cancer (CRPC). However, drug resistance has hindered its further application. Moreover, CRPC is frequently prone to metastasis, particularly to bone (BmCRPC). <b>Methods:</b> To investigate the involvement of phosphatase and tensin homolog deleted on chromosome 10 (<i>PTEN</i>) deletion and C-X-C motif chemokine receptor 2 (CXCR2) overexpression in Enz-resistant CRPC and BmCRPC, we constructed a bisphosphonate (BP) lipid-like material with high bone affinity (GB4-BPL) for the codelivery of a PTEN plasmid (pPTEN) and CXCR2 siRNA (siCXCR2) to BmCRPC. <b>Results:</b> GB4-BPL demonstrated twice the bone metastasis-targeting ability of GB4-lipo (which lacks bisphosphonate modification) while maintaining a gene transfection efficiency comparable to that of Lipo8000 and exhibiting significantly lower cytotoxicity. Moreover, siCXCR2 and pPTEN loaded in GB4-BPL (GB4-BPL@siCXCR2/pPTEN) synergistically inhibited tumor growth and metastasis, highly enhancing the effect of Enz by 69.45% in the Enz-resistant model. Furthermore, GB4-BPL@siCXCR2/pPTEN significantly reduced the numbers of MDSCs, Tregs, and M2-like TAMs by 55.01%, 64.75%, and 52.53%, respectively, while increasing the proportions of M1 macrophages, NK cells, and CD8<sup>+</sup> T cells by 1.65-, 1.40-, and 4.60-fold, respectively. In addition, this nanosystem reduced skeletal-related events. <b>Conclusions:</b> Our studies demonstrated the potential of GB4-BPL for delivering siCXCR2/pPTEN to tumor and bone metastatic sites. GB4-BPL@siCXCR2/pPTEN alone or in combination with Enz could provide a new strategy for the treatment of drug-resistant BmCRPC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8488-8508"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144970137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TheranosticsPub Date : 2025-07-25eCollection Date: 2025-01-01DOI: 10.7150/thno.119422
Nishat I Tabassum, Sharmelee Selvaraji, Yibo Fan, Vernise Jt Lim, Xiangru Cheng, Xiangyuan Peng, Aayushi Arora, Vismitha Rajeev, Julian Ratcliffe, Chad J Johnson, Keshava K Datta, Rohan Lowe, Mansour Ebrahimi, Quynh Nhu Dinh, T Michael De Silva, Christopher G Sobey, Peiyan Wong, Eddie Feng-Ju Weng, Dong-Gyu Jo, Christopher P Chen, Mitchell K P Lai, Thiruma V Arumugam
{"title":"Intermittent fasting reprograms the brain proteome to prevent synaptic degeneration and cognitive impairment in vascular dementia.","authors":"Nishat I Tabassum, Sharmelee Selvaraji, Yibo Fan, Vernise Jt Lim, Xiangru Cheng, Xiangyuan Peng, Aayushi Arora, Vismitha Rajeev, Julian Ratcliffe, Chad J Johnson, Keshava K Datta, Rohan Lowe, Mansour Ebrahimi, Quynh Nhu Dinh, T Michael De Silva, Christopher G Sobey, Peiyan Wong, Eddie Feng-Ju Weng, Dong-Gyu Jo, Christopher P Chen, Mitchell K P Lai, Thiruma V Arumugam","doi":"10.7150/thno.119422","DOIUrl":"https://doi.org/10.7150/thno.119422","url":null,"abstract":"<p><p><b>Rationale:</b> Vascular dementia (VaD), driven by chronic cerebral hypoperfusion (CCH), leads to synaptic degeneration and cognitive decline, yet mechanisms linking vascular dysfunction to synaptic loss remain unclear. Intermittent fasting (IF) has emerged as a potential intervention, but its effects on synaptic integrity in VaD are unknown. This study aims to investigate the effects of IF against synaptic degeneration and cognitive impairment induced by CCH. Methods: Bilateral common carotid artery stenosis (BCAS) was employed to induce chronic CCH by placing 0.18 mm micro-coils around each common carotid artery in mice. To assess temporal differences, the coils remained in place for 1, 7, 14, or 30 days. IF was implemented for 16 hours daily over three months prior to BCAS induction. Cognitive impairment was evaluated using the Barnes maze test. White matter lesions (WMLs) and neuronal loss were assessed using Luxol fast blue and cresyl violet staining, respectively. Immunoblotting and immunohistochemistry were performed to quantify synaptic protein levels. Synaptic integrity was examined using transmission electron microscopy. Proteomic analysis of the hippocampus was conducted to investigate molecular adaptations to IF following CCH. <b>Results:</b> We demonstrate that a 16-hour IF regimen preserves cognitive function and synaptic density despite persistent hypoperfusion. Behavioral assays revealed that IF prevented spatial memory deficits in BCAS mice, while electron microscopy confirmed synaptic preservation without altering baseline architecture. Surprisingly, key synaptic protein levels remained unchanged, suggesting IF protects synaptic function rather than abundance. Proteomic profiling revealed dynamic hippocampal adaptations under IF, including upregulation of synaptic stabilizers, enhanced GABAergic signaling, and suppression of neuroinflammatory mediators. CCH induced microglial engulfment of synapses, suggesting a role in complement-mediated synaptic pruning. Temporal pathway analysis revealed IF's multi-phase neuroprotection: early synaptic reinforcement, mid-phase metabolic optimization, and late-phase suppression of chronic neuroinflammation. <b>Conclusion:</b> These findings establish IF as a potent modulator of synaptic resilience in VaD, acting through coordinated preservation of synaptic structure, inhibition of inflammatory synapse loss, and metabolic reprogramming. Our results highlight IF's potential as a non-pharmacological strategy to combat vascular cognitive impairment by targeting the synaptic vulnerability underlying dementia progression.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8429-8450"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144969912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
TheranosticsPub Date : 2025-07-25eCollection Date: 2025-01-01DOI: 10.7150/thno.112332
Zhonghao Mao, Yan Tian, Lisha Wu, Yu Zhang
{"title":"Epitranscriptomic mechanisms and implications of RNA m<sup>5</sup>C modification in cancer.","authors":"Zhonghao Mao, Yan Tian, Lisha Wu, Yu Zhang","doi":"10.7150/thno.112332","DOIUrl":"https://doi.org/10.7150/thno.112332","url":null,"abstract":"<p><p>Cancer is an extremely complex disease characterized by abnormal cell growth due to genetic and environmental factors. With the rise of the field of epigenetic transcriptomics, 5-methylcytidine (m<sup>5</sup>C) modification has been identified as one of the most common chemical modifications occurring in various RNA types. The writers, erasers, and readers of m<sup>5</sup>C modification regulate cancer initiation, progression, and therapeutic responses, such as the proliferation, metastasis, angiogenesis, metabolic reprogramming, immune escape, and therapeutic resistance of tumour cells, by regulating RNA stability, translation, nuclear export, and splicing processes. In this review, we elucidate the biological process of m<sup>5</sup>C modification, summarize the abnormal expression of RNA-modifying proteins (RMPs) in common malignant tumours, explore their functional effects on malignant hallmarks of cancer and molecular mechanisms, and prospect the potential clinical application value of m<sup>5</sup>C.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 16","pages":"8404-8428"},"PeriodicalIF":13.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144969899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}