Theranostics最新文献

{"title":"RAB7 protects against ischemic heart failure via promoting non-canonical TUFM mitophagy pathway.","authors":"Yuling Sun, Wei Wang, Mingyan Li, Wen Guan, Zhimin Gao, Luping Wang, Guanlan Lou, Ao Shen, Jiangbin Wu, Xiyong Yu, Panxia Wang, Xiaoqian Wu","doi":"10.7150/thno.104124","DOIUrl":"10.7150/thno.104124","url":null,"abstract":"<p><p><b>Rationale:</b> Cardiomyocyte apoptosis critically contributes to ischemic heart failure (IHF) progression. While the endosome-lysosome system governs cellular homeostasis, the functional significance of its master regulator RAB7 in cardiac pathophysiology remains unexplored. <b>Methods:</b> Using myocardial infarction (MI) models via left anterior descending coronary artery ligation in cardiomyocyte-specific RAB7 knockout mice and adeno-associated virus-mediated RAB7 overexpression models, we assessed cardiac function and adverse remodeling through echocardiography and pathophysiological assessment. Mitophagy flux was quantified using mt-Keima mice and confocal imaging. Molecular mechanisms were dissected through immunoprecipitation coupled with mass spectrometry (IP-MS) analysis and molecular experiment validation. <b>Results:</b> RAB7 expression decreased in ischemic myocardium. Cardiomyocyte-specific RAB7 ablation exacerbated while RAB7 overexpression attenuated post-MI cardiac dysfunction and maladaptive remodeling. RAB7 enhanced mitophagic clearance of damaged mitochondria, reducing cardiomyocyte apoptosis under ischemic stress both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, TUFM, a mitochondrial translation elongation factor, was identified as a novel effector of RAB7. RAB7 facilitated the recruitment of TUFM and LC3 to damaged mitochondria, thereby enhancing mitophagy. TUFM knockdown significantly diminished the protective effects of RAB7 on mitophagy and cardiomyocyte survival. Finally, administration of ML-098, a chemical RAB7 activator, promoted mitophagy and mitigated IHF progression in mice. <b>Conclusion:</b> We identify RAB7 as a novel coordinator of cardioprotective mitophagy through TUFM-mediated machinery assembly. The RAB7-TUFM axis represents a therapeutic target for IHF that warrants further clinical evaluation.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6753-6767"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529629","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":"Blocking TRPM4 alleviates pancreatic acinar cell damage via an NMDA receptor-dependent pathway in acute pancreatitis.","authors":"Yifan Ren, Qing Cui, Wuming Liu, Hangcheng Liu, Tao Wang, Hongwei Lu, Yi Lv, Rongqian Wu","doi":"10.7150/thno.116520","DOIUrl":"10.7150/thno.116520","url":null,"abstract":"<p><p><b>Background:</b> Mitochondrial dysfunction caused by Ca²⁺ overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca²⁺, and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. <b>Methods:</b> We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for <i>in vivo</i> studies. For <i>in vitro</i> studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. <i>Trpm4</i> gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. <b>Conclusions:</b> TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6901-6918"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529556","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":"Repurposing methimazole to promote coronary collateral circulation through MAPK1-mediated macrophage polarization via ferroptosis.","authors":"Ling-Ping Zhu, Wei He, Ke-Chuan Lin, Dan Wang, Lin-Lin Wang, Shuai Li, Mei-Lian Yao, Jing Chen, Mei-Fang Chen, Guo-Gang Zhang, Chuan-Chang Li, Ling-Ping Zhu, Yong-Ping Bai","doi":"10.7150/thno.111606","DOIUrl":"10.7150/thno.111606","url":null,"abstract":"<p><p><b>Rationale</b>: Coronary collateral circulation (CCC) is essential for myocardial recovery after infarction, yet effective strategies to enhance CCC formation are scarce. In this study, we aimed to identify potential FDA-approved drugs that can promote CCC after MI injury. <b>Methods</b>: Candidate drugs were screened through multiple analyses using cMap and public CCC-related databases. Male C57BL/6J mice underwent myocardial infarction (MI) surgery, and 3D micro-CT imaging and immunostaining for smooth muscle actin (SMA) in the watershed region of the heart were employed to evaluate CCC formation. Cardiac function was assessed through Masson's trichrome staining and cardiac ultrasonography. Macrophage polarization was analyzed using flow cytometry, qRT‒PCR, and immunostaining. Additionally, a macrophage and THP-1 cell coculture system was established to simulate the <i>in vivo</i> microenvironment, and mitochondrial morphology was assessed using electron microscopy. <b>Results</b>: Our screen revealed that methimazole (MMI) efficiently promotes CCC formation by driving the polarization of macrophages from the proinflammatory M1-like phenotype to the proangiogenic M2-like phenotype. <i>In vitro</i>, MMI enhanced the differentiation of THP-1 cells into M2-like macrophages and increased VEGFA secretion. Mechanistically, molecular docking studies confirmed a direct interaction between MMI and MAPK1, leading to the suppression of the MAPK1/ROS axis and inhibition of ferroptosis, which facilitated M2 polarization. Furthermore, <i>in vivo</i>, honokiol (HK), a MAPK activator, reversed the effects of MMI on CCC, confirming the pivotal role of the MAPK1 pathway. <b>Conclusions</b>: This study reveals a novel therapeutic role for MMI in promoting CCC formation following MI through the modulation of macrophage polarization via the MAPK1/ROS axis-mediated inhibition of ferroptosis. These findings highlight the potential of MMI as a strategy for enhancing cardiac repair and advancing collateral circulation therapies for ischemic heart disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6686-6701"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529557","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":"Combination of KRAS ASO and RIG-I agonist in extracellular vesicles transforms the tumor microenvironment towards effective treatment of KRAS-dependent cancers.","authors":"Cao Dai Phung, Trinh T T Tran, Brendon Zhi Jie Yeo, Rebecca Carissa Prajogo, Evelyn Saudjana, Eric Yew Meng Yeo, Chang Gao, Phuong H D Nguyen, Migara Kavishka Jayasinghe, Xuan T T Dang, Celest Phang Lixuan, Trinh Mai Nguyen, Boya Peng, Anh Hong Le, Tram T T Nguyen, Gloria Mei En Chan, Yuin-Han Loh, Boon Cher Goh, Wai Leong Tam, Glenn Kunnath Bonney, Dahai Luo, Minh T N Le","doi":"10.7150/thno.105519","DOIUrl":"10.7150/thno.105519","url":null,"abstract":"<p><p><b>Rationale</b>: Mutations in the <i>KRAS</i> gene drive many cancers, yet targeting <i>KRAS</i> mutants remains a challenge. Here, we address this hurdle by utilizing a nucleic acid-based therapeutic strategy delivered via extracellular vesicles (EVs) to simultaneously inhibit <i>KRAS</i> mutants and activate the RIG-I pathway, aiming to enhance anti-tumor immunity. <b>Methods</b>: Antisense oligonucleotides against <i>KRAS</i> mutants (<i>KRAS</i> ASOs) and RIG-I agonist immunomodulatory RNA (immRNA) were loaded into EVs and administered to <i>KRAS</i>-mutant cancer models. The therapeutic effects were assessed in colorectal and non-small cell lung cancer (NSCLC) tumor models, as well as patient-derived pancreatic cancer organoids. Immune responses were evaluated by analyzing tumor microenvironment's changes, dendritic cell activation, and T cell memory formation. The treatment efficacy was evaluated based on the tumor development and overall survival. <b>Results</b>: The KRAS-ASO and immRNA combination treatment induced immunogenic tumor cell death and upregulated interferons in <i>KRAS</i>-dependent cancers. In a colorectal tumor model, the therapy shifted the tumor microenvironment to an immunogenic state, activated dendritic cells in sentinel lymph nodes, and promoted memory T cell formation. In an aggressive NSCLC model, the treatment resulted in a strong anti-tumor activity and extended survival without any adverse effects. Validation in patient-derived pancreatic cancer organoids confirmed the clinical translation potential of this approach. <b>Conclusions</b>: EV-mediated delivery of ASOs and immRNA effectively inhibits <i>KRAS</i> mutants and activates RIG-I, leading to a robust anti-tumor immune response. This strategy holds promise for effectively treating <i>KRAS</i>-driven cancers and improving clinical outcomes.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6818-6838"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529591","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":"Enhancing hair regrowth using rapamycin-primed mesenchymal stem cell-derived exosomes.","authors":"Manju Shrestha, Tiep Tien Nguyen, Rabyya Kausar, Dinesh Chaudhary, Ines Ferdiana Puspitasari, Hu-Lin Jiang, Hyung-Sik Kim, Simmyung Yook, Jee-Heon Jeong","doi":"10.7150/thno.107659","DOIUrl":"10.7150/thno.107659","url":null,"abstract":"<p><p><b>Rationale:</b> Hair loss affects millions globally, with limited effective treatments available and significant psychological impacts. Mesenchymal stem cells (MSCs) and MSC-derived exosomes hold therapeutic potential by modulating cellular communication, reducing inflammation, and supporting hair follicular regeneration. Rapamycin, a mechanistic target of rapamycin (mTOR) inhibitor, enhances MSC therapeutic potential by promoting the release of growth factors and signaling molecules. Thus, this study explores the benefit of priming effect of rapamycin on enhancing the function of MSC-derived exosomes to promote hair regrowth in a depilation-induced murine model. <b>Methods:</b> MSCs were primed with rapamycin, and exosomes were extracted from the MSC-conditioned media using ultrafiltration and poly (ethylene glycol) (PEG) precipitation. Dermal fibroblasts were treated with several doses of exosomes to evaluate the <i>in vitro</i> effect of rapamycin-primed MSC-derived exosomes (REXO). The depilated mice were administered exosomes via intradermal route and the hair regrowth was monitored for 15 days, followed by gene expression analysis and histological examination. <b>Results:</b> Dermal fibroblasts treated with REXO showed a higher proliferation rate and an increase in genes related to Wnt/β-catenin signaling, autophagy, and growth factors compared to non-primed MSC-derived exosomes (CEXO). <i>In vivo</i> REXO therapy via intradermal injection to the depilated areas in mice enhanced hair follicle development, hair density, and hair activation markers compared with the control and naive exosome treatments. <b>Conclusion:</b> REXO therapy effectively enhances hair regrowth thus this approach could offer a clinically effective therapy for hair loss treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6938-6956"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529596","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":"Single-cell transcriptomics of vascularized human brain organoids decipher lineage-specific stress adaptation in fetal hypoxia-reoxygenation injury.","authors":"Simeng Yi, Min Huang, Chunmei Xian, Xi Kong, Shigang Yin, Jianhua Peng, Yong Zhang, Xiuju Du, Yong Jiang, Bingqing Xie, Huangfan Xie","doi":"10.7150/thno.117001","DOIUrl":"10.7150/thno.117001","url":null,"abstract":"<p><p><b>Rationale:</b> Fetal hypoxia, a major contributor to neonatal mortality, induces complex neurovascular disruptions in developing brains, yet human-specific cellular mechanisms remain poorly understood due to limitations in existing models. This study establishes an advanced vascularized human cortical organoid (vhCO) model to decode cell type-specific injury mechanisms and therapeutic targets during hypoxia-reoxygenation. <b>Methods:</b> We developed vhCOs by integrating cortical and vascular organoids, recapitulating mid-to-late gestational neurodevelopment with diverse lineages-neural progenitors, neurons, microglia, and functional vasculature with blood-brain barrier properties. Hypoxia-reoxygenation experiments were conducted on vhCOs, followed by single-cell transcriptomic profiling to dissect cellular responses. <b>Results:</b> Key findings include: (1) Lineage-specific vulnerabilities: astrocyte precursors exhibited developmental arrest, while immature GABAergic neurons (Subtype I) underwent neurogenic collapse. Microglia displayed a biphasic inflammatory response-initially suppressed, then hyperactivated post-reoxygenation, diverging from animal models; (2) Hypoxia memory persisted in non-neural cells (pericytes, fibroblasts), driving compartment-specific vascular remodeling via Notch signaling and collagen deposition; (3) Rewired neural-non-neural crosstalk networks (e.g., IGF2-IGF2R, LGALS3-MERTK, Wnts-SFRP2) revealed novel repair targets inaccessible to conventional models. <b>Conclusions:</b> By prioritizing single-cell resolution, this study delineates human-specific neurovascular pathophysiology and stress adaptation networks in hypoxic brain injury. The vhCO platform bridges translational gaps, offering a paradigm for precision therapeutics and advancing research on developmental brain disorders.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"7001-7024"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529558","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":"MTX2 facilitates PKM2 tetramerization to promote cardiac glucose metabolism and protects the heart against ischemia/reperfusion injury.","authors":"Yueyang Li, Yu Li, Yang Li, Yufan Jiang, Miao Wang, Mingyi Wang, Jie Liu, Mingrui Ma, Xiaofeng Zhai, Li Yi, Tao Chen, Zhenyu Xiong, Yundai Chen","doi":"10.7150/thno.110162","DOIUrl":"10.7150/thno.110162","url":null,"abstract":"<p><p><b>Rationale:</b> Myocardial ischemia reperfusion (I/R) injury is a major cause of adverse outcomes following revascularization therapy. Although alterations in metabolic activities during reperfusion have been implicated, the molecular mechanisms underlying the pathogenesis of I/R injury remain elusive. Metaxin 2 (MTX2), initially identified as a core component of protein import complexes, has recently been characterized in diverse cellular functions. Nevertheless, its involvement in myocardial I/R injury has yet to be fully elucidated. In this study, we aim to evaluate the role and the underlying mechanism of MTX2 in I/R injury. <b>Methods:</b> The myocardial I/R model was established, and the protein levels of MTX2 were determined at different time points following coronary occlusion. Loss-of-function and gain-of-function strategies were applied via genetic ablation or intra-myocardial adenovirus injection to ascertain the role of MTX2 in myocardial I/R injury. RNA sequencing, seahorse metabolic analysis, and mass spectrometry were conducted to uncover the underlying molecular mechanisms. <b>Results:</b> We observed that the expression of MTX2 was significantly decreased in I/R hearts. Tamoxifen-induced cardiomyocyte-specific deletion of <i>Mtx2</i> led to aggravated myocardial I/R injury, resulting in impaired cardiac oxidative phosphorylation and glycolysis. Mechanistically, dimeric PKM2, a less active pyruvate kinase form compared with tetrameric PKM2, was found to be dramatically accumulated in <i>Mtx2</i> deficiency mice after myocardial I/R surgery. The TOM37 domain of MTX2 interacted directly with PKM2 to promote PKM2 tetramerization, thereby modulating glucose metabolic flux. Pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, rescued the metabolic and functional outcomes of I/R in <i>Mtx2</i> deficiency mice. <b>Conclusions:</b> Our results identified, for the first time, a cardioprotective role of MTX2 in modulating cardiac glucose metabolism by facilitating PKM2 tetramerization. Targeting metabolic homeostasis by restoring MTX2 might be a promising therapeutic strategy to mitigate myocardial I/R injury.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6737-6752"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529623","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":"Bioinspired nano-micron hydrogel microspheres for periodontitis therapy through synergistic multi-targeted remodeling of microenvironment.","authors":"Siqi Zhou, Yuxin Zhang, Liwen Zheng, Chang Liu, Jiajun Chen, Yaxian Liu, Shidian Ran, Tong-Chuan He, Mengqin Gu, Si Wu, Fugui Zhang, Hongmei Zhang","doi":"10.7150/thno.112782","DOIUrl":"10.7150/thno.112782","url":null,"abstract":"<p><p><b>Background:</b> Periodontitis is a prevalent oral inflammatory disease that leads to alveolar bone resorption and tooth loss. It is hard to control and prone to recurrence. Current treatments often fall short due to deep, tortuous periodontal pockets and antibiotic-resistant bacteria, such as <i>Fusobacterium nucleatum</i> (<i>F. nucleatum</i>). Notably, current clinical therapies fail to simultaneously fulfill three critical objectives: robust antimicrobial efficacy, potent anti-inflammatory activity, and effective periodontal regenerative capacity. <b>Methods:</b> Inspired by the structure of the lotus flower, nano/micron-combined hydrogel microspheres (PDA/BBR@Gel@BMP9-PDLSC), encapsulating polydopamine (PDA) nanoparticles carrying berberine (PDA/BBR) and BMP9-infected PDLSCs (BMP9-PDLSC), were developed. <b>Results</b>: Microspheres exhibited excellent biocompatibility and sustained drug release, along with significant antibacterial, anti-inflammatory, and bone tissue regenerative effects. <i>In vivo</i> studies confirmed their efficacy in treating calvaria defects and periodontitis with persistent <i>F. nucleatum</i> infection, showing superior new bone formation and anti-inflammatory effects without organ toxicity. Notably, our study demonstrated that the anti-inflammation and osteogenesis effects were due to the synergistic effects of BBR and BMP9 released by PDA/BBR@Gel@BMP9-PDLSC microspheres. RNA-Seq and Western blot analysis showed that BBR and BMP9 synergistically reduced inflammation and promoted bone formation by regulating key genes involved in TNF, TGF-β, and PPAR signaling pathways. <b>Conclusions:</b> Our study provides a novel approach for comprehensively treating periodontitis with antibacterial, anti-inflammatory, and bone tissue regenerative effects.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6857-6881"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529555","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":"Tailorable bimetallic nanozyme mitigates intervertebral disc degeneration by inhibiting oxidative stress and inflammageing.","authors":"Anran Zhang, Haiyang Gao, Xianglong Chen, Pengzhi Shi, Zhangrong Cheng, Yuhang Chen, Wang Wu, Wenbo Wu, Cao Yang, Yukun Zhang","doi":"10.7150/thno.108592","DOIUrl":"10.7150/thno.108592","url":null,"abstract":"<p><p><b>Rationale:</b> Scavenging reactive oxygen species (ROS), modulating extracellular matrix (ECM) anabolism, and preventing senescence of nucleus pulposus cells (NPCs) are crucial factors of treatment approaches for intervertebral disc degeneration (IDD). However, addressing these issues simultaneously has been challenging due to the interactions among the various pathological factors in the disc microenvironment. <b>Methods:</b> Herein, we utilize self-assembly technology and the excellent drug-carrying potential of mesoporous Prussian blue to design a tailorable bimetallic nanozyme platform of a Mn-modified mesoporous Prussian blue loaded with Cibotium barometz (MPB-Mn3-CB) for the treatment of IDD. <b>Results:</b> The enhancement of multiple antioxidant enzyme activities by MPB-Mn3-CB is ascribed to the lower activation energy of the MnN₄ active site compared to the FeN₄ active site. <i>In vitro</i> and <i>in vivo</i> experiments show that MPB-Mn3-CB efficiently scavenges ROS, promotes ECM synthesis, and rescues the senescent phenotype of NPCs by inhibiting the P53 pathway. <b>Conclusion:</b> This work addresses the specific microenvironmental challenges in severe IDD by synchronously tackling multiple interacting pathological factors and provides a potential therapeutic strategy by multifunctional bimetallic nanozyme for IDD treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6957-6982"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529559","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":"Divergent splicing factor SRSF1 signaling promotes inflammation post-CME: the SRSF1/ENPP3 axis acts via inhibition of BRD4 O-GlcNAcylation to enhance NF-κB activation and accelerate heart failure.","authors":"Chen-Kai Hu, Lei He, Wan-Zhong Huang, Yuan Huang, Ri-Xin Dai, Chen Chang, Jun-Xiong Qiu, Qiang Wu, Qiang Su","doi":"10.7150/thno.115402","DOIUrl":"10.7150/thno.115402","url":null,"abstract":"<p><p><b>Rationale:</b> Coronary microembolization (CME) is a severe medical condition that occurs during acute coronary syndrome, leading to myocardial inflammation, apoptosis, and cardiac dysfunction. The research investigated SRSF1 biological functions during myocardial inflammation caused by CME and its underlying mechanisms. <b>Methods:</b> CME models were established in rats injected with microspheres in the left ventricle and oxygen-glucose deprivation (OGD)-exposed cardiomyocytes. RT-qPCR, Western blotting and immunohistochemical staining were used to evaluate the expression of target molecules. Myocardial apoptosis was detected by flow cytometry. The direct binding between SRSF1 and ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) was verified by RIP and TRAP. Protein interaction was determined by Co-IP. The dual-luciferase reporter assay measured inflammatory cytokine transcription levels. Myocardial injury was assessed by HE staining and ultrasound examinations. The study used ELISA to measure inflammatory cytokines and cardiac troponin I (cTnI) levels. <b>Results:</b> SRSF1 expression was strikingly enhanced in CME models. Knockdown of SRSF1 effectively restrained NF-κB-mediated myocardial inflammation through increasing ENPP3 mRNA/lncRNA ENPP3 ratio by regulating alternative splicing of ENPP3 pre-mRNA. The GlcNAcylation of bromodomain-containing protein 4 (BRD4) was reduced during CME, which increased BRD4 protein level to trigger NF-κB-mediated inflammation. SRSF1/ENPP3 axis inhibited the GlcNAcylation of BRD4 in CME. Myocardial-specific knockout of SRSF1 restored cardiac function and restrained myocardial inflammation in CME rats by inactivation of the ENPP3/BRD4/NF-κB pathway. <b>Conclusions:</b> SRSF1 facilitates CME-induced myocardial inflammation by up-regulating ENPP3/lncRNA ENPP3 ratio to suppress GlcNAcylation of BRD4, suggesting SRSF1 inhibition as a promising therapeutic strategy for CME.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 14","pages":"6839-6856"},"PeriodicalIF":12.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529593","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}