Theranostics最新文献

{"title":"Hepatocyte-specific Smad4 deficiency inhibits hepatocarcinogenesis by promoting CXCL10/CXCR3-dependent CD8⁺- T cell-mediated anti-tumor immunity.","authors":"Xin Xin, Zhao Li, Xuanxuan Yan, Ting Liu, Zuyin Li, Zhuomiaoyu Chen, Xinlong Yan, Fanxin Zeng, Lingling Hou, Jinhua Zhang","doi":"10.7150/thno.97276","DOIUrl":"https://doi.org/10.7150/thno.97276","url":null,"abstract":"<p><p><b>Rationale:</b> Sma mothers against decapentaplegic homologue 4 (Smad4) is a key mediator of the transforming growth factor β (TGF-β) pathway and plays complex and contradictory roles in hepatocellular carcinoma (HCC). However, the specific role of Smad4 in hepatocytes in regulating hepatocarcinogenesis remains poorly elucidated. <b>Methods:</b> A diethylnitrosamine/carbon tetrachloride-induced HCC model was established in mice with hepatocyte-specific Smad4 deletion (Alb^Smad4-/-) and liver tumorigenesis was monitored. Immune cell infiltration was examined by immunofluorescence and fluorescence activated cell sorting (FACS). Cytokine secretion, glycolysis, signal pathway, and single-cell RNA sequencing were analysed for mechanism. <b>Results:</b> Alb^Smad4-/- mice exhibited significantly fewer and smaller liver tumor nodules, less fibrosis, reduced myeloid-derived suppressor cell infiltration and increased CD8⁺ T cell infiltration. Smad4 deletion in hepatocytes enhanced C-X-C motif ligand 10 (CXCL10) secretion, promoting tumor necrosis factor-α (TNF-α) production in CD8⁺ T cells. The loss of Smad4 activated the CXCL10/mammalian target of rapamycin (mTOR)/lactate dehydrogenase A (LDHA) pathway, which increased glycolytic activity in CD8⁺ T cells. HCC patients with high Smad4 expression exhibited decreased CD8⁺ T cell infiltration and altered glycolysis. <b>Conclusion:</b> Our results demonstrate that Smad4 in hepatocytes promotes hepatocarcinogenesis and is a potential and candidate target for the prevention and therapy of HCC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354352","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":"Selenoprotein S maintains intestinal homeostasis in ulcerative colitis by inhibiting necroptosis of colonic epithelial cells through modulation of macrophage polarization.","authors":"Yujie Yao, Tong Xu, Xiaojing Li, Xu Shi, Hao Wu, Ziwei Zhang, Shiwen Xu","doi":"10.7150/thno.97005","DOIUrl":"https://doi.org/10.7150/thno.97005","url":null,"abstract":"<p><p><b>Rationale:</b> Macrophage polarization plays an important role in the inflammatory regulation of ulcerative colitis (UC). In this context, necroptosis is a type of cell death that regulates intestinal inflammation, and selenoprotein S (SelS) is a selenoprotein expressed in intestinal epithelial cells and macrophages that prevents intestinal inflammation. However, the underlying mechanisms of SelS in both cell types in regulating UC inflammatory responses remain unclear. Therefore, the direct effect of SelS deficiency on necroptosis in colonic epithelial cells (CECs) was investigated. In addition, whether SelS knockdown exacerbated intestinal inflammation by modulating macrophage polarization to promote necroptosis in CECs was assessed. <b>Methods:</b> The UC model of SelS knockdown mice was established with 3.5% sodium dextran sulfate, and clinical indicators and colon injury were evaluated in the mice. Moreover, SelS knockdown macrophages and CECs cultured alone/cocultured were treated with IL-1β. The M1/M2 polarization, NF-κB/NLRP3 signaling pathway, oxidative stress, necroptosis, inflammatory cytokine, and tight junction indicators were analyzed. In addition, co-immunoprecipitation, liquid chromatography-mass spectrometry, laser confocal analysis, and molecular docking were performed to identify the interacting proteins of SelS. The GEO database was used to assess the correlation of SelS and its target proteins with macrophage polarization. The intervention effect of four selenium supplements on UC was also explored. <b>Results: U</b>biquitin A-52 residue ribosomal protein fusion product 1 (Uba52) was identified as a potential interacting protein of SelS and SelS, Uba52, and yes-associated protein (YAP) was associated with macrophage polarization in the colon tissue of patients with UC. SelS deficiency in CECs directly induced reactive oxygen species (ROS) production, necroptosis, cytokine release, and tight junction disruption. SelS deficiency in macrophages inhibited YAP ubiquitination degradation by targeting Uba52, promoted M1 polarization, and activated the NF-κB/NLRP3 signaling pathway, thereby exacerbating ROS-triggered cascade damage in CECs. Finally, exogenous selenium supplementation could effectively alleviate colon injury in UC. <b>Conclusion:</b> SelS is required for maintaining intestinal homeostasis and that its deletion enhances necroptosis in CECs, which is further exacerbated by promoting M1 macrophage polarization, and triggers more severe barrier dysfunction and inflammatory responses in UC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354361","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 RNA-Seq analysis of molecular changes during radiation-induced skin injury: the involvement of Nur77.","authors":"Tao Yan, Ping Yang, Hao Bai, Bin Song, Yulan Liu, Jiajia Wang, Yuehua Zhang, Wenling Tu, Daojiang Yu, Shuyu Zhang","doi":"10.7150/thno.100417","DOIUrl":"https://doi.org/10.7150/thno.100417","url":null,"abstract":"<p><p><b>Introduction:</b> Ionizing radiation has been widely used in industry, medicine, military and agriculture. Radiation-induced skin injury is a significant concern in the context of radiotherapy and accidental exposure to radiation. The molecular changes at the single-cell level and intercellular communications during radiation-induced skin injury are not well understood. <b>Methods:</b> This study aims to illustrate this information in a murine model and human skin samples from a radiation accident using single-cell RNA sequencing (scRNA-Seq). We further characterize the functional significance of key molecule, which may provide a potential therapeutic target. ScRNA-Seq was performed on skin samples from a nuclear accident patient and rats exposed to ionizing radiation. Bioinformatic tools were used to analyze the cellular heterogeneity and preferential mRNAs. Comparative analysis was performed to identify dysregulated pathways, regulators, and ligand-receptor interactions in fibroblasts. The function of key molecule was validated in skin cells and in three mouse models of radiation-induced skin injury. <b>Results:</b> 11 clusters in human skin and 13 clusters of cells in rat skin were depicted respectively. Exposure to ionizing radiation caused changes in the cellular population (upregulation of fibroblasts and endothelial cells, downregulation of keratinocytes). Fibroblasts and keratinocytes possessed the most interaction pairs with other cell lineages. Among the five DEGs common to human and rat skins, <i>Nur77</i> was highly expressed in fibroblasts, which mediated radiosensitivity by cell apoptosis and modulated crosstalk between macrophages, keratinocytes and endothelial cells in radiation-induced skin injury. In animal models, <i>Nur77</i> knock-out mice (<i>Nur77</i> ^-/-) showed more severe injury after radiation exposure than wild-type counterparts in three models of radiation-induced skin injury with complex mechanisms. <b>Conclusion:</b> The study reveals a single-cell transcriptional framework during radiation-induced skin injury, which provides a useful resource to uncover key events in its progression. <i>Nur77</i> is a novel target in radiation-induced skin injury, which provides a potential therapeutic strategy against this disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354362","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":"Hypoxia-induced TGFBI maintains glioma stem cells by stabilizing EphA2.","authors":"Zirong Chen, Junhong Wang, Peng Peng, Guohao Liu, Minhai Dong, Xiaolin Zhang, Yang Zhang, Xue Yang, Lijun Wan, Wang Xiang, Suojun Zhang, Bin Zhang, Qiuxia Wu, Xingjiang Yu, Feng Wan","doi":"10.7150/thno.95141","DOIUrl":"https://doi.org/10.7150/thno.95141","url":null,"abstract":"<p><p><b>Rationale:</b> Glioma stem cells (GSCs) have emerged as pivotal drivers of tumor malignancy, sustained by various microenvironmental factors, including immune molecules and hypoxia. In our previous study, we elucidated the significant role of transforming growth factor beta-induced protein (TGFBI), a protein secreted by M2-like tumor-associated macrophages, in promoting the malignant behavior of glioblastoma (GBM) under normoxic conditions. Building upon these findings, the objective of this study was to comprehensively explore the crucial role and underlying mechanisms of autocrine TGFBI in GSCs under hypoxic conditions. <b>Methods:</b> We quantified TGFBI expression in glioma specimens and datasets. <i>In vitro</i> and <i>in vivo</i> assays were employed to investigate the effects of TGFBI on sustaining self-renewal and tumorigenesis of GSCs under hypoxia. RNA-seq and LC-MS/MS were conducted to explore TGFBI signaling mechanisms. <b>Results:</b> TGFBI is preferentially expressed in GSCs under hypoxic conditions. Targeting TGFBI impair GSCs self-renewal and tumorigenesis. Mechanistically, TGFBI was upregulated by HIF1α in GSCs and predominantly activates the AKT-c-MYC signaling pathway in GSCs by stabilizing the EphA2 protein through preventing its degradation. <b>Conclusion:</b> TGFBI plays a crucial role in maintaining the stem cell properties of GSCs in the hypoxic microenvironment. Targeting the TGFBI/EphA2 axis emerges as a promising and innovative strategy for GBM treatment, with the potential to improve the clinical outcomes of patients.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354354","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":"Cardiomyocyte-derived small extracellular vesicle: a new mechanism driving diabetic cardiac fibrosis and cardiomyopathy.","authors":"Yu Li, Yunhui Du, Yang Liu, Xiuhuan Chen, Xinxin Li, Yanru Duan, Yanwen Qin, Huirong Liu, Xinliang Ma, Shaoping Nie, Huina Zhang","doi":"10.7150/thno.99507","DOIUrl":"https://doi.org/10.7150/thno.99507","url":null,"abstract":"<p><p><b>Rationale:</b> Diabetic cardiomyopathy is one of the major diabetic cardiovascular complications in which fibrosis plays a critical pathogenetic role. However, the precise mechanisms by which diabetes triggers cardiac fibrosis in the heart remain elusive. Small extracellular vesicles (sEVs) play an important role in the cellular communication. Nevertheless, whether and how diabetes may adversely alter sEVs-mediated cardiomyocyte-fibroblast communication, promoting diabetic cardiac fibrosis and contributing to diabetic cardiomyopathy, has not been previously investigated. <b>Methods and results:</b> High-fat diet (HFD)-induced and genetic (<i>db/db</i>) type 2 diabetic models were utilized. Cardiomyocyte sEVs (Myo-sEVs) were isolated by ultracentrifugation. Normal cardiomyocyte-derived Myo-sEVs attenuated diabetic cardiac fibrosis <i>in vitro</i> and <i>in vivo</i> and improved cardiac diastolic function. In contrast, diabetic cardiomyocyte-derived Myo-sEVs significantly exacerbated diabetic cardiac fibrosis and worsened diastolic function. Unbiased miRNA screening analysis revealed that miR-194-3p was significantly reduced in diabetic Myo-sEVs. Additional <i>in vitro</i> and <i>in vivo</i> experiments demonstrated that miR-194-3p is a novel upstream molecule inhibiting TGFβR2 expression and blocking fibroblast-myofibroblast conversion. Administration of miR-194-3p mimic or agomiR-194-3p significantly reduced diabetic cardiac fibrosis <i>in vitro</i> and <i>in vivo</i>, and attenuated diabetic cardiomyopathy. <b>Conclusion:</b> Our study demonstrates for the first time that cardiomyocyte-derived miR194-3p inhibits TGFβ-mediated fibroblast-to-myofibroblast conversion, acting as an internal break against cardiac fibrosis. Diabetic downregulation of sEV-mediated miR-194-3p delivery from cardiomyocytes to fibroblasts contributes to diabetic cardiac fibrosis and diabetic cardiomyopathy. Pharmacological or genetic restoration of this system may be a novel therapy against diabetic cardiomyopathy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354346","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":"Ferroptosis at the nexus of metabolism and metabolic diseases.","authors":"Shuangwen Li, Guixiang Zhang, Jiankun Hu, Yan Tian, Xianghui Fu","doi":"10.7150/thno.100080","DOIUrl":"https://doi.org/10.7150/thno.100080","url":null,"abstract":"<p><p>Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a crucial regulator of human physiology and pathology. Increasing evidence showcases a reciprocal relationship between ferroptosis and dysregulated metabolism, propagating a pathogenic vicious cycle that exacerbates pathology and human diseases, particularly metabolic disorders. Consequently, there is a rapidly growing interest in developing ferroptosis-based therapeutics. Therefore, a comprehensive understanding of the intricate interplay between ferroptosis and metabolism could provide an invaluable resource for mechanistic insight and therapeutic development. In this review, we summarize the important metabolic substances and associated pathways in ferroptosis initiation and progression, outline the cascade responses of ferroptosis in disease development, overview the roles and mechanisms of ferroptosis in metabolic diseases, introduce the methods for ferroptosis detection, and discuss the therapeutic perspectives of ferroptosis, which collectively aim to illustrate a comprehensive view of ferroptosis in basic, translational, and clinical science.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354351","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":"ROCK inhibitor enhances mitochondrial transfer via tunneling nanotubes in retinal pigment epithelium.","authors":"Jing Yuan, Fangxuan Chen, Dan Jiang, Zehua Xu, Hang Zhang, Zi-Bing Jin","doi":"10.7150/thno.96508","DOIUrl":"https://doi.org/10.7150/thno.96508","url":null,"abstract":"<p><p><b>Rationale:</b> Tunnel nanotube (TNT)-mediated mitochondrial transport is crucial for the development and maintenance of multicellular organisms. Despite numerous studies highlighting the significance of this process in both physiological and pathological contexts, knowledge of the underlying mechanisms is still limited. This research focused on the role of the ROCK inhibitor Y-27632 in modulating TNT formation and mitochondrial transport in retinal pigment epithelial (RPE) cells. <b>Methods:</b> Two types of ARPE19 cells (a retinal pigment epithelial cell line) with distinct mitochondrial fluorescently labeled, were co-cultured and treated with ROCK inhibitor Y-27632. The formation of nanotubes and transport of mitochondria were assessed through cytoskeletal staining and live cell imaging. Mitochondrial dysfunction was induced by light damage to establish a model, while mitochondrial function was evaluated through measurement of oxygen consumption rate. The effects of Y-27632 on cytoskeletal and mitochondrial dynamics were further elucidated through detailed analysis. <b>Results:</b> Y-27632 treatment led to an increase in nanotube formation and enhanced mitochondrial transfer among ARPE19 cells, even following exposure to light-induced damage. Our analysis of cytoskeletal and mitochondrial distribution changes suggests that Y-27632 promotes nanotube-mediated mitochondrial transport by influencing cytoskeletal remodeling and mitochondrial movement. <b>Conclusions</b>: These results suggest that Y-27632 has the ability to enhance mitochondrial transfer via tunneling nanotubes in retinal pigment epithelium, and similarly predict that ROCK inhibitor can fulfill its therapeutic potential through promoting mitochondrial transport in the retinal pigment epithelium in the future.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354360","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":"Developing an enhanced chimeric permuted intron-exon system for circular RNA therapeutics.","authors":"Lei Wang, Chunbo Dong, Weibing Zhang, Xu Ma, Wei Rou, Kai Yang, Tong Cui, Shaolong Qi, Lijun Yang, Jun Xie, Guocan Yu, Lianqing Wang, Xiaoyuan Chen, Zhida Liu","doi":"10.7150/thno.98214","DOIUrl":"https://doi.org/10.7150/thno.98214","url":null,"abstract":"<p><p><b>Rationale</b>: Circular RNA (circRNA) therapeutics hold great promise as an iteration strategy in messenger RNA (mRNA) therapeutics due to their inherent stability and durable protein translation capability. Nevertheless, the efficiency of RNA circularization remains a significant constraint, particularly in establishing large-scale manufacturing processes for producing highly purified circRNAs. Hence, it is imperative to develop a universal and more efficient RNA circularization system when considering synthetic circRNAs as therapeutic agents with prospective clinical applications. <b>Methods:</b> We initially developed a chimeric RNA circularization system based on the original permuted intron-exon (PIE) and subsequently established a high-performance liquid chromatography (HPLC) method to obtain highly purified circRNAs. We then evaluated their translational ability and immunogenicity. The circRNAs expressing human papillomavirus (HPV) E7 peptide (43-62aa) and dimerized receptor binding domain (dRBD) from SARS-CoV-2 were encapsulated within lipid nanoparticles (LNPs) as vaccines, followed by an assessment of the <i>in vivo</i> efficacy through determination of antigen-specific T and B cell responses, respectively. <b>Results:</b> We have successfully developed a universal chimeric permuted intron-exon system (CPIE) through engineering of group I self-splicing introns derived from Anabaena pre-tRNA^Leu or T4 phage thymidylate (Td) synthase gene. Within CPIE, we have effectively enhanced RNA circularization efficiency. By utilizing size exclusion chromatography, circRNAs were effectively separated, which exhibit low immunogenicity and sustained potent protein expression property. <i>In vivo</i> data demonstrate that the constructed circRNA vaccines can elicit robust immune activation (B cell and/or T cell responses) against tumor or SARS-CoV-2 and its variants in mouse models. <b>Conclusions:</b> Overall, we provide an efficient and universal system to synthesize circRNA <i>in vitro</i>, which has extensive application prospect for circRNA therapeutics.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354348","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":"Air bag-embedded MIL-101(Fe) metal-organic frameworks for an amplified tumor microenvironment activation loop through strategic delivery of iron ions and lentinan.","authors":"Tao Han, Yan Sun, Xi Jiang, Chengming Gong, Fei Kong, Yi Luo, Chang Ge, Congyan Liu, Yuping Liu, Yanfei Mou, Huangqin Zhang, Jianming Ju, Yan Chen, Ding Qu","doi":"10.7150/thno.99303","DOIUrl":"https://doi.org/10.7150/thno.99303","url":null,"abstract":"<p><p><b>Background:</b> Iron-based nanocarriers have demonstrated potential in redirecting tumor associated macrophages (TAMs) polarization towards the M1 phenotype, critical for activating the tumor microenvironment (TME) in triple negative breast cancer (TNBC). However, their real-world effectiveness is curtailed by insufficient Fe^2+/3+ exposure and the absence of suitable synergists in tumors. <b>Methods:</b> We introduce an air bag-embedded iron-based MIL-101 metal-organic frameworks (MOF_MIL-101(Fe)) for igniting the TME in TNBC through bubble-driven tumoral codelivery of Fe^2+/3+ and lentinan. This system, named HM/Ef/LNT-MOF_MIL-101(Fe), features nano-sized MOF_MIL-101(Fe) as the core, embedded NaHCO₃ as a pH-triggered air bag, electrostatically-adsorbed lentinan forming the inner shell, and a shield shell with 4T1&red blood cell hybrid membrane. <b>Results:</b> HM/Ef/LNT-MOF_MIL-101(Fe) can mitigate non-specific capture in the bloodstream but respond to the acidic tumor milieu, rapidly generating a burst of CO₂ bubbles to disassemble MOF_MIL-101(Fe). Upon entering tumors, lentinan-induced interferon-γ (IFN-γ) enable Fe^2+/3+ facilitating an enhanced ferroptosis and Fenton-like reaction, pushing TAMs towards M1 polarization via the \"IFN-γ-ferroptosis-ROS-Caspase-3\" pathway. Moreover, HM/Ef/LNT-MOF_MIL-101(Fe) increases the infiltration of T lymphocytes and decreases regulatory T cells. These cascading immune responses synergistically foster a loop of amplified TME activation based on TAMs M1 polarization, showcasing notable advancements in anticancer effectiveness and promise for various combination therapies. <b>Conclusion:</b> This study utilizes an \"embedded air-bag\" strategy to achieve strategic codelivery of Fe^2+/3+ and lentinan, providing a new tool for engineering the TME.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354345","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":"Knocking out USP7 attenuates cardiac fibrosis and endothelial-to-mesenchymal transition by destabilizing SMAD3 in mice with heart failure with preserved ejection fraction.","authors":"Shuai Yuan, Zimu Wang, Shun Yao, Yanyan Wang, Zhonglei Xie, Jingfeng Wang, Xueting Yu, Yu Song, Xiaotong Cui, Jingmin Zhou, Junbo Ge","doi":"10.7150/thno.97767","DOIUrl":"https://doi.org/10.7150/thno.97767","url":null,"abstract":"<p><p><b>Background</b>: Heart failure with preserved ejection fraction (HFpEF) is a predominant type of heart failure. Exploring new pathogenesis and identifying potential novel therapeutic targets for HFpEF is of paramount importance. <b>Methods</b>: HFpEF mouse model was established by the \"Multiple-hit\" strategy, in that 18- to 22-month-old female C57B6/J mice fed with a high-fat diet were further challenged with chronic infusion of Angiotensin II. RNA sequencing analysis showed that USP7 was significantly increased in the heart of HFpEF mice. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, in conjunction with co-immunoprecipitation (Co-IP) techniques, identified expression of SMAD3, the key molecule of endothelial-to-mesenchymal transition (EndMT), was also significantly elevated. USP7 endothelium-specific knockout mice was generated to investigate the involvement of USP7 in HFpEF. The biological significance of the interaction between USP7 and SMAD3 was further explored. <b>Results</b>: USP7 promotes EndMT and cardiac fibrosis by binding to SMAD3 directly via its UBL (Ubiquitin-like) domain and cysteine at position 223 of USP7, leading SMAD3 deubiquitination to maintain the stability of SMAD3 by removing the K63 ubiquitin chain and preventing the degradation of SMAD3 by proteasomal process. USP7 also promotes SMAD3 phosphorylation and nuclear translocation, thereby aggravating EndMT and cardiac fibrosis. Endothelium-specific USP7 knockout led to improvement of HFpEF phenotypes and reduction of cardiac fibrosis. Overexpression of SMAD3 in endothelium-specific knockout HFpEF mice reversed the protective effects of USP7 knockout in this HFpEF mouse model. <b>Conclusion:</b> Our results indicated that USP7 is one of the key pathogenic molecules of HFpEF, and knocking out USP7 could attenuate HFpEF injury by promoting the degradation of SMAD3. USP7 and SMAD3 inhibition might be potential therapeutic options for HFpEF.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354355","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}