Theranostics最新文献

{"title":"Lipopolysaccharide-induced DNA damage response activates DNA-PKcs to drive actin cytoskeleton disruption and cardiac microvascular dysfunction in endotoxemia.","authors":"Ying Tan, Yue Ouyang, Lushan Xiao, Jianming Huang, Fuye Li, Zisheng Ma, Chuhong Tan, Weibin Feng, Erica Davis, Yaoping Tang, Xing Chang, Haixia Li","doi":"10.7150/thno.111266","DOIUrl":"10.7150/thno.111266","url":null,"abstract":"<p><p><b>Rationale:</b> Sepsis-induced cardiomyopathy is characterized by microvascular injury, which is linked to lipopolysaccharide (LPS)-induced DNA damage response (DDR). This study investigates the role of DNA-PKcs, a key enzyme in the DDR pathway, in driving actin disruption and microvascular dysfunction following LPS exposure. <b>Methods:</b> We analyzed diverse transcriptomic datasets from septic human and murine models using bioinformatics tools to assess DDR pathway activation, correlations, and prognosis. <i>In vivo</i>, LPS-challenged mice were treated with inhibitors of DNA-PKcs or mitochondrial fission, and we evaluated cardiac function, microvascular integrity, mitochondrial status, and actin polymerization. <b>Results:</b> Bioinformatic analyses consistently revealed significant activation of the DDR pathway and upregulation of key genes across diverse septic models. Notably, elevated DDR pathway activity was significantly correlated with poor 28-day survival in human sepsis patients. Single-cell analysis localized this DDR gene upregulation predominantly to cardiac endothelial cells (ECs), fibroblasts, and macrophages during sepsis. Within septic capillary ECs, DDR pathway activity scores strongly correlated spatially and functionally with heightened mitochondrial fission and cytoskeletal remodeling pathway activities. <i>In vivo</i> experiments confirmed that LPS induced severe systolic and diastolic dysfunction, microvascular damage, and mitochondrial fragmentation, as well as significant actin depolymerization. Inhibition of DNA-PKcs with NU7441 markedly attenuated all these LPS-induced pathologies, improving cardiac function, preserving microvascular structure, preventing mitochondrial fragmentation, and normalizing related gene expression and actin cytoskeleton stability. Additionally, inhibiting mitochondrial fission with Mdivi-1 significantly ameliorated LPS-induced cardiac dysfunction and microvascular injury. <b>Conclusions:</b> Our findings suggest that LPS triggers a DNA-PKcs-dependent DDR that promotes mitochondrial fragmentation and actin disruption, particularly in cardiac ECs, contributing to sepsis-induced cardiomyopathy. Targeting DNA-PKcs or mitochondrial fission may hold therapeutic potential for the treatment of sepsis-induced cardiomyopathy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5969-5997"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043448","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":"Short-term starvation inhibits CD36 N-glycosylation and downregulates USP7 UFMylation to alleviate RBPJ-maintained T cell exhaustion in liver cancer.","authors":"Banglun Pan, Siyan Chen, Hao Wu, Xiaoxia Zhang, Zhu Zhang, Dongjie Ye, Yuxin Yao, Yue Luo, Xinyu Zhang, Xiaoqian Wang, Nanhong Tang","doi":"10.7150/thno.110567","DOIUrl":"10.7150/thno.110567","url":null,"abstract":"<p><p><b>Rationale:</b> Short-term starvation (STS) has been shown to enhance the sensitivity of tumors to chemotherapy while concurrently safeguarding normal cells from its detrimental side effects. Nonetheless, the extent to which STS relies on the anti-tumor immune response to impede the progression of hepatocellular carcinoma (HCC) remains uncertain. <b>Methods:</b> In this study, we employed mass cytometry, flow cytometry, immunoprecipitation, immunoblotting, CUT&Tag, RT-qPCR, and DNA pull-down assays to evaluate the relationship between STS and T-cell antitumor immunity in HCC. <b>Results:</b> We demonstrated that STS alleviated T cell exhaustion in HCC. This study elucidated the mechanism by which STS blocked CD36 N-glycosylation, leading to the upregulation of AMPK phosphorylation and the downregulation of USP7 UFMylation, thus enhancing ubiquitination and destabilized USP7. Consequently, diminished USP7 levels facilitated the ubiquitination and subsequent degradation of RBPJ, thereby inhibiting T cell exhaustion through the IRF4/TNFRSF1B axis. From a therapeutic standpoint, STS not only suppressed the growth of patient-derived orthotopic xenografts but also enhanced their sensitivity to immunotherapy. <b>Conclusions:</b> These findings uncovered a novel mechanism by which N-glycosylation participated in UFMylation/ubiquitination to regulate T cell exhaustion, and we underscored the potential of targeting USP7 and RBPJ in anti-tumor immunotherapy strategies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5931-5952"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000494","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":"Nuclear damage-induced DNA damage response coupled with IFI16-driven ECM remodeling underlies dilated cardiomyopathy.","authors":"Qingyong He, Xing Chang, Hui Zhang, Qianying Hao, Jianguo Zhi, Hongshuo Shi, Yingjie Tian, Hao Zhou, Ying Tan, Junmeng Zheng, Junxiong Qiu, Jun Tao","doi":"10.7150/thno.112247","DOIUrl":"10.7150/thno.112247","url":null,"abstract":"<p><p><b>Rationale:</b> Dilated cardiomyopathy (DCM) is a severe cardiac condition characterized by ventricular dilation and systolic dysfunction, often leading to heart failure. While the DNA damage response (DDR) pathway is increasingly implicated in DCM pathogenesis, the precise mechanisms linking DDR activation to specific pathological features like adverse extracellular matrix (ECM) remodeling and fibrosis remain poorly understood. Interferon-inducible protein 16 (IFI16), a known DNA sensor involved in DDR and inflammatory signaling, emerges as a potential mediator in this process. This study aimed to investigate the role of the DDR-IFI16 axis in DCM, specifically exploring its connection to ECM dysregulation and cardiac dysfunction, and to evaluate its potential as a therapeutic target. <b>Methods:</b> W This study integrated bioinformatics analyses of human cardiac transcriptomic datasets with experimental validation in a doxorubicin-induced murine DCM model. Cardiac function was assessed by echocardiography. Key molecular pathways were investigated using qPCR, ELISA, and enrichment analyses. Mechanistic roles were tested via pharmacological DDR inhibition <i>in vivo</i> and targeted <i>IFI16</i> siRNA knockdown <i>in vitro</i>, followed by analysis of fibrosis, cell viability, and cytotoxicity markers. <b>Results:</b> Bioinformatic analyses consistently revealed activation of DDR and cytosolic DNA sensing pathways across human iPSC-CM models and <i>ex vivo</i> DCM heart tissue. WGCNA identified a key gene module strongly associated with DCM, co-enriched for DDR, DNA replication, and ECM/TGF-β signaling pathways. Single-cell RNA-seq analysis confirmed significant <i>IFI16</i> upregulation in human DCM samples. High <i>IFI16</i> expression strongly correlated with pathways governing 'Extracellular matrix organization' and key fibrotic genes. Experimental validation in the doxorubicin mouse model confirmed DDR activation. Crucially, <i>in vivo</i> treatment with the DDR inhibitor NU7441 significantly attenuated <i>IFI16</i> upregulation, ameliorated cardiac dysfunction, and decreased cardiac fibrosis markers. Complementarily, <i>in vitro</i> knockdown of <i>IFI16</i> significantly reduced pro-fibrotic markers, increased cell viability, and decreased cell injury. <b>Conclusions:</b> Our findings delineate a novel pathogenic axis in DCM where nuclear stress-induced DDR activation drives the upregulation of the DNA sensor IFI16. IFI16 acts as a critical mediator linking DDR signaling to pathological ECM remodeling and fibrosis. Pharmacological inhibition of the upstream DDR pathway effectively mitigates IFI16 induction, attenuates cardiac fibrosis, and improves cardiac function. This study identifies the DDR-IFI16-ECM remodeling axis as a crucial contributor to DCM pathogenesis and highlights its potential as a therapeutic target for mitigating adverse cardiac remodeling and dysfunction.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5998-6021"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987584","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":"A self-assembled and H₂O₂-activatable hybrid nanoprodrug for lung infection and wound healing therapy.","authors":"Rui Zhang, Danhua Mao, Yiyong Fu, Rong Ju, Guoqing Wei","doi":"10.7150/thno.114344","DOIUrl":"10.7150/thno.114344","url":null,"abstract":"<p><p><b>Background:</b> The pursuit of effective antibacterial strategies aimed at mitigating pathogenic bacterial infections while minimising drug resistance remains of paramount importance. A combinational therapeutic strategy that integrates distinct treatment components can enhance overall efficacy and mitigate undesired effects, thereby exhibiting considerable promise in combating bacterial infections. <b>Methods:</b> In this study, a meticulously engineered self-assembling hybrid nanoprodrug (CPBP NPs) has been devised, functioning as a hybrid prodrug of Ciprofloxacin (Cip) and hydroxybenzyl alcohol (HBA). <b>Results:</b> CPBP molecules can generate nanoassemblies via self-assembly and subsequently undergo decomposition to synchronously release Cip and HBA upon hydrogen peroxide (H₂O₂) exposure. The CPBP NPs exert antibacterial and anti-inflammatory properties through the controlled release of Cip and HBA, while also facilitating the scavenging of reactive oxygen species. These CPBP NPs exhibit broad-spectrum antibacterial activity against both Gram-negative bacteria (<i>E. coli</i>, 98.4%) and Gram-positive bacteria (<i>S. aureus</i>, 98.5%). Notably, CPBP NPs not only accumulate in the lungs to facilitate organ-specific infection treatment but also expedite the healing process of infected wounds. <b>Conclusions:</b> Consequently, this H₂O₂-activatable hybrid nanoprodrug, possessing excellent biocompatibility, holds substantial promise for advancing clinical applications in managing bacterial infections.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5953-5968"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144011622","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":"Dual prophylactic and therapeutic potential of iPSC-based vaccines and neoantigen discovery in colorectal cancer.","authors":"Si-Han Jwo, Shang-Kok Ng, Chin-Tzu Li, Shao-Peng Chen, Li-Yu Chen, Pin-Jung Liu, Huai-Jie Wang, Jr-Shiuan Lin, Chun-Jung Ko, Cheng-Fan Lee, Chun-Hao Wang, Xiaoming Ouyang, Lin Wang, Tzu-Tang Wei","doi":"10.7150/thno.111400","DOIUrl":"10.7150/thno.111400","url":null,"abstract":"<p><p><b>Rationale:</b> Induced pluripotent stem cells (iPSCs) share transcriptomic similarities with cancer cells and express tumor-specific and tumor-associated antigens, highlighting their potential as cancer vaccines. Our previous study demonstrated that an iPSC-based vaccine effectively prevented tumor growth in various mouse models, including melanoma, breast, lung, and pancreatic cancers. However, the underlying mechanisms and the therapeutic efficacy of the iPSC-based vaccine remain unclear. Colorectal cancer (CRC), the third most common cancer with a rising incidence worldwide, presents an urgent need for novel strategies to prevent and treat CRC. <b>Methods:</b> Allograft mouse models were established to evaluate the antitumor effects of the iPSC-based vaccine. CpG oligonucleotide (ODN) 1826 served as a vaccine adjuvant. Bulk RNA-Sequencing (RNA-Seq) and the Microenvironment Cell Population counter (MCP-Counter) algorithm were performed to analyze transcriptomic changes. Liquid chromatography-mass spectrometry (LC-MS) combined with in silico strategies was employed to identify potential antigen proteins. Chinese Hamster Ovary (CHO-K1) models were utilized to express candidate neoantigen proteins. Mouse bone marrow-derived dendritic cells (BMDCs) were used to investigate T cell priming in response to iPSC-associated proteins. Immune cell profiles were characterized by flow cytometry. <b>Results:</b> The combination of CpG and iPSC vaccination demonstrated both prophylactic and therapeutic efficacy in reducing tumor growth in CRC mouse models. Vaccination significantly increased CD8⁺ T cell infiltration within tumor regions, while T cell depletion abrogated the antitumor effects, underscoring the critical role of T cells in mediating these responses. Proteomic analysis identified two iPSC-associated proteins, heterogeneous nuclear ribonucleoprotein U (HNRNPU) and nucleolin (NCL), as key drivers of the observed immune responses. Vaccination with HNRNPU or NCL, in combination with CpG, enhanced dendritic cell activation, induced antigen-specific CD8⁺ T cell cytotoxicity, and promoted the formation of central memory CD8⁺ T cells, collectively leading to significant CRC tumor shrinkage. <b>Conclusions:</b> Our findings reveal potential mechanisms underlying the efficacy of iPSC-based vaccines in cancer immunotherapy. Additionally, HNRNPU and NCL were identified as key antigen proteins in iPSC, demonstrating promise for the development of peptide-based vaccines for both the prevention and treatment of CRC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5890-5908"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062286","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":"A small molecule esculetin accelerates postprandial lipid clearance involving activation of C/EBPβ and CD36-mediated phagocytosis by adipose tissue macrophages.","authors":"Gang Wang, Zhaokai Li, Wei Ni, Heng Ye, Yang Liu, Linjian Chen, Lin Wang, Changjiang Liu, Jingyu Chen, Xuchao Wang, Xue Ding, Longshan Zhao, Xiaofeng Ge, Yan Wang, Yuanchao Ye, Toshihiko Kiwa, Linghe Zang, Jin Wang, Cuilian Dai, Binbin Liu","doi":"10.7150/thno.110207","DOIUrl":"10.7150/thno.110207","url":null,"abstract":"<p><p><b>Rationale</b>: Adipose tissue buffers dietary lipids to maintain postprandial lipid homeostasis. Adipose tissue macrophages (ATMs) mediate the phagocytosis of postprandial lipids from the exogenous diet, generating high-density lipoprotein (HDL) particles that facilitate lipid circulation and excretion. However, the underlying mechanisms remain poorly understood. This study investigates the effects of esculetin, a coumarin compound, on postprandial cholesterol circulation and excretion following a high-fat meal. <b>Methods</b>: Mice were fed a lipid-rich meal for three days to assess the effects of esculetin on postprandial lipid circulation, using serum lipid profiling and metabolomics analysis. Epididymal white adipose tissue (eWAT) removal and flow cytometry were performed to analyze ATMs and confirm their role in mediating esculetin's effects on postprandial lipemia. Epigenetic profiling, transcriptome analysis, chromatin immunoprecipitation, and Terahertz chemical microscopy were employed to elucidate the molecular targets and mechanisms of esculetin. <b>Results</b>: Esculetin significantly elevates postprandial HDL cholesterol levels to values comparable to pitavastatin and modifies serum metabolites involved in bile-mediated cholesterol excretion, leading to increased bile acid concentrations in the bile. This effect is mediated by an increased ratio and phagocytic activity of a subset of ATMs expressing the scavenger receptor CD36, as eWAT removal and CD36 blockade inhibit this response. Furthermore, esculetin enhances the uptake of oxidized LDL via CD36, as demonstrated in cultured macrophages, and induces epigenetic changes controlled by the key transcription factor C/EBPβ, accompanied by increased C/EBPβ binding to the <i>Cd36</i> promoter. A direct interaction between esculetin and C/EBPβ was observed using Terahertz chemical microscopy. Additionally, the activation of C/EBPβ by esculetin in ATMs was confirmed <i>in vivo</i>. <b>Conclusion</b>: Esculetin accelerates postprandial lipid circulation by binding to C/EBPβ and enhancing CD36-dependent phagocytosis in ATMs.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5910-5930"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038473","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":"pH-responsive nano-vaccine combined with anti-PD-1 antibodies for enhanced immunotherapy of breast cancer.","authors":"Ning Wang, Hong Yu, Jianqiao Yin, Xiaopeng Yu","doi":"10.7150/thno.107200","DOIUrl":"10.7150/thno.107200","url":null,"abstract":"<p><p><b>Objective:</b> This study aimed to investigate the therapeutic potential and underlying mechanisms of a novel pH-responsive nano-vaccine in combination with anti-Programmed Cell Death Protein 1 (PD-1) antibodies for the treatment of breast cancer (BC), with a focus on tumor growth inhibition, metastasis prevention, and immune microenvironment modulation. <b>Methods:</b> A pH-responsive amphiphilic diblock copolymer was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization and conjugated with STING agonist ADU-S100 and mannose to specifically target dendritic cells (DCs). The nano-vaccine was further formulated with antigen peptides and polyethyleneimine (PEI) to enhance antigen delivery. Its particle size, stability, and surface charge were characterized using dynamic light scattering (DLS) and zeta potential analysis. <i>In vitro</i>, the immunostimulatory capacity of the nano-vaccine was evaluated via flow cytometry (FCM) analysis of DC activation markers. <i>In vivo</i>, mouse immune and tumor recurrence models were used to assess the its effects on T-cell activation, tumor suppression, and immune memory induction. The therapeutic efficacy of nano-vaccine/anti-PD-1 combination therapy was further assessed. <b>Results:</b> The nano-vaccine efficiently activated DCs and promoted antigen presentation, as indicated by increased CD80, CD86, and MHC-II expression <i>in vitro</i>. In mouse models, it effectively inhibited tumor growth, induced antigen-specific T-cell responses, and suppressed recurrent and metastatic tumor progression. The combination with anti-PD-1 antibodies further enhanced tumor control, immune cell infiltration, and survival rates compared to monotherapy. <b>Conclusion:</b> The pH-responsive nano-vaccine combined with anti-PD-1 antibodies showed remarkable synergistic effects in BC treatment, highlighting its potential to enhance immune checkpoint blockade therapy and offer a promising strategy for clinical applications in solid tumors.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"6022-6043"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043798","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":"Sulfated chitosan directs the recovery of ischemic stroke by attenuating the inflammatory cascade.","authors":"Zehua Gao, Xuanlin Wang, Qiyong Mei, Tong Shen, Jing Wang, Changsheng Liu","doi":"10.7150/thno.111681","DOIUrl":"10.7150/thno.111681","url":null,"abstract":"<p><p><b>Background:</b> Ischemic stroke is considered a fatal ischemic disease with high mortality and morbidity. Acute ischemic stroke is a cascade of inflammatory reactions, which not only causes vascular degeneration but also leads to neurological disorders. During this period, the rapid response of neutrophil-dominated granulocytes releases cytokines and chemokines to affect tissue repair. Thus, effective regulation of neutrophils appears to be the key in treating major organ injuries associated with inflammation. <b>Methods:</b> This study developed a semisynthetic sulfated chitosan (SCS) associated with the functional sulfated groups. The immunoregulatory effects of SCS on neutrophils were tested by Real-Time Quantitative Reverse Transcription (RT-PCR), ELISA and immunofluorescence staining at gene and protein levels <i>in vitro</i>. Flow cytometry, WB and PCR were used to study the effect of neutrophils on macrophages, indicating the regulation of the inflammatory cascade by SCS. Acute ischemic stroke model was established to verify the effectiveness and the regulation of inflammatory cascade of SCS. Finally, the lower limb ischemia model was used to verify the universality of SCS in the treatment of ischemic diseases, especially with regard to acute inflammatory-related major organ damage. <b>Results:</b> SCS can not only promote neutrophil apoptosis, but also enable neutrophils to produce vascular-related subsets to regulate immunity and promote angiogenesis. Neutrophil stimulated by SCS mediated macrophage polarization via IL-10-induced Stat3 signaling pathway to weaken the inflammatory cascade. In animal models of ischemic hind limb and ischemic stroke, SCS had demonstrated its ability to shorten the acute inflammatory period, as indicated by neutrophil, and accelerate the subsequent repair period characterized by the presence of M₂ macrophages. Additionally, SCS effectively inhibits the expression of MMP-9 to provide a favorable environment for rapid extracellular matrix reconstruction. Encouragingly, treatment with SCS had been shown to reduce the expansion of the infarct volume by approximately 20% in our experiments. <b>Conclusion:</b> This study underscores the effect of SCS in regulating the heterogeneity of neutrophils in order to suppress the initiation of inflammation to treat ischemic stroke. Crucially, our approach relies on non-exogenous growth factors and cells, highlighting its remarkable potential for clinical translatability in the treatment of major organ injuries.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5870-5889"},"PeriodicalIF":12.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144032859","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":"Targeting neutrophil extracellular traps in cancer progression and metastasis.","authors":"Ji Zhang, Changhong Miao, Hao Zhang","doi":"10.7150/thno.111096","DOIUrl":"10.7150/thno.111096","url":null,"abstract":"<p><p>Neutrophils serve as pivotal effectors and regulators of the intricate immune system. Their contributions are indispensable, encompassing the obliteration of pathogens and a significant role in both cancer initiation and progression. Conversely, malignancies profoundly affect neutrophil activity, maturation, and lifespans. Cancer cells manipulate their biology to enhance or suppress the key functions of neutrophils. This manipulation is one of the most remarkable defensive mechanisms used by neutrophils, including the formation of neutrophil extracellular traps (NETs). NETs are filamentous structures comprising DNA, histones, and proteins derived from cytotoxic granules. In this review, we discuss the bidirectional interplay in which cancer elicits NET formation, and NETs concurrently facilitate cancer progression. Here, we discuss how vascular dysfunction and thrombosis induced by neutrophils and NETs contribute to an elevated risk of mortality from cardiovascular complications in patients with cancer. Ultimately, we propose a series of therapeutic strategies that hold promise for effectively targeting NETs in clinical settings.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5846-5869"},"PeriodicalIF":12.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987655","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":"Promotion of Cx26 mutants located in TM4 region for membrane translocation successfully rescued hearing loss.","authors":"Yan-Jun Zong, Xiao-Zhou Liu, Xin-Yu Shi, Zheng-Dong Zhao, Yu Sun","doi":"10.7150/thno.112225","DOIUrl":"10.7150/thno.112225","url":null,"abstract":"<p><p><b>Rationale:</b> The <i>GJB2</i> gene, which encodes connexin 26 (Cx26), is recognized as the leading cause of non-syndromic hereditary hearing loss. In clinical settings, a total of 131 Cx26 mutations have been identified in association with hearing loss. Certain Cx26 mutants display normal structural and functional properties but fail to translocate to the plasma membrane. Enhancing the membrane localization of these mutants may provide a promising strategy for rescuing hearing loss and hair cell degeneration. <b>Methods:</b> This study investigated the membrane localization of Cx26 using <i>in vitro</i> cell lines, cultured cochlear explants, and <i>in vivo</i> murine models. Key proteins involved in the membrane localization of Cx26 were identified and validated through immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP). Additionally, cell lines and murine models harboring Cx26 mutants were developed to evaluate the effects of Narciclasine on enhancing the membrane localization of these mutants, as well as its potential to rescue hearing loss. <b>Results:</b> The membrane localization of Cx26 was dependent on the integrity of the intracellular transport network consisting of microtubules, actin microfilaments, and the Golgi apparatus. Additionally, SPTBN1 played a significant role in this process. The transmembrane domain 4 (TM4) region exhibited a strong association with the membrane localization of Cx26, and Cx26 mutants located in TM4 region retained in the cytoplasm. Narciclasine promoted cytoskeletal development, thereby enhancing the membrane localization of Cx26 mutants retained in the cytoplasm. This process helped to reconstruct the inner ear gap junction network and rescue hearing loss and hair cell degeneration. <b>Conclusion:</b> These findings present that enhancing the membrane localization of Cx26 mutants can significantly improve auditory function. This strategy offers a potential therapeutic approach for addressing hereditary sensorineural hearing loss associated with <i>GJB2</i> mutations.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 12","pages":"5801-5825"},"PeriodicalIF":12.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040074","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}