Theranostics最新文献

{"title":"DLGAP5 enhances bladder cancer chemoresistance by regulating glycolysis through MYC stabilization.","authors":"Zhao Deng, Fenfang Zhou, Mingxing Li, Wan Jin, Jingtian Yu, Gang Wang, Kaiyu Qian, Lingao Ju, Yi Zhang, Yu Xiao, Xinghuan Wang","doi":"10.7150/thno.102730","DOIUrl":"10.7150/thno.102730","url":null,"abstract":"<p><p><b>Rationale:</b> Bladder cancer (BLCA), one of the most lethal urological tumors, exhibits high rates of recurrence and chemoresistance, particularly to gemcitabine (GEM). Understanding the mechanisms of GEM resistance is crucial for improving therapeutic outcomes. Our study investigates the role of DLGAP5 in promoting GEM resistance through modulation of glycolysis and MYC protein stability in BLCA cells. <b>Methods:</b> We utilized various BLCA cell lines and clinical tissue samples to analyze the impact of DLGAP5 on GEM resistance. Through biochemical assays, protein interaction studies, and gene expression analyses, we examined how DLGAP5 interacts with USP11 and MYC, assessed the effects on MYC deubiquitination and stability. The influence of these interactions on glycolytic activity and GEM resistance was also evaluated via mouse subcutaneous xenograft model and spontaneous BLCA model. <b>Results:</b> Our findings indicate that DLGAP5 enhances GEM resistance by stabilizing MYC protein via deubiquitination, a process mediated by USP11. DLGAP5 was found to facilitate the interaction between USP11 and MYC, promoting MYC-driven transcription of DLGAP5 itself, thereby creating a positive feedback loop. This loop leads to sustained MYC accumulation and increased glycolytic activity, contributing to GEM resistance in BLCA cells. <b>Conclusion:</b> The study highlights the critical role of DLGAP5 in regulating MYC protein stability and suggests that disrupting the DLGAP5-USP11-MYC axis may provide a novel therapeutic approach to overcome GEM resistance in BLCA. DLGAP5 represents a potential target for therapeutic intervention aimed at mitigating chemoresistance in bladder cancer BLCA.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2375-2392"},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483614","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":"Glucose homeostasis controls N-acetyltransferase 10-mediated ac4C modification of HK2 to drive gastric tumorigenesis.","authors":"Qiang Wang, Mengmeng Li, Chen Chen, Lei Xu, Yao Fu, Jiawen Xu, Chuanjun Shu, Bo Wang, Zhangding Wang, Changyu Chen, Tao Song, Shouyu Wang","doi":"10.7150/thno.104310","DOIUrl":"10.7150/thno.104310","url":null,"abstract":"<p><p><b>Rationale:</b> Abnormal metabolic states contribute to a variety of diseases, including cancer. RNA modifications have diverse biological functions and are implicated in cancer development, including gastric cancer (GC). However, the direct relationship between glucose homeostasis and 4-acetylcytosine (ac4C) modification in GC remains unclear. <b>Methods:</b> The prognostic value of RNA acetyltransferase NAT10 expression was evaluated in a human GC cohort. Additionally, preoperative PET/CT data from GC patients and Micro-PET/CT imaging of mice were employed to assess the relationship between NAT10 and glucose metabolism. The biological role of NAT10 in GC was investigated through various experiments, including GC xenografts, organoids, and a conditional knockout (cKO) mouse model. The underlying mechanisms were examined using dot blotting, immunofluorescence staining, co-immunoprecipitation, and high-throughput sequencing, among other techniques. <b>Results:</b> Glucose deprivation activates the autophagy-lysosome pathway, leading to the degradation of NAT10 by enhancing its interaction with the sequestosome 1 (SQSTM1)/microtubule-associated protein 1 light chain 3 alpha (LC3) complex, ultimately resulting in a reduction of ac4C modification. Furthermore, the levels of ac4C and NAT10 are elevated in GC tissues and correlate with poor prognosis. A strong correlation exists between NAT10 levels and 18F-FDG uptake in GC patients. Furthermore, NAT10 drives glycolytic metabolism and gastric carcinogenesis <i>in vitro</i> and <i>in vivo</i>. Mechanistically, NAT10 stimulates ac4C modification at the intersection of the coding sequence (CDS) and 3' untranslated region (3'UTR) of hexokinase 2 (HK2) mRNA, enhancing its stability and activating the glycolytic pathway, thereby driving gastric tumorigenesis. <b>Conclusion:</b> Our findings highlight the critical crosstalk between glucose homeostasis and the ac4C epitranscriptome in gastric carcinogenesis. This finding offers a potential strategy of targeting NAT10/HK2 axis for the treatment of GC patients, especially those with highly active glucose metabolism.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2428-2450"},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483853","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":"Inhibition of macrophage inflammasome assembly and pyroptosis with GC-1 ameliorates acute lung injury.","authors":"Bin Li, Jingyi Liu, Wanyu He, Yanlin Zhou, Man Zhao, Cong Xia, Xiaoyue Pan, Zhihua Ji, Ruoyu Duan, Hui Lian, Kai Xu, Guoying Yu, Lan Wang","doi":"10.7150/thno.101866","DOIUrl":"10.7150/thno.101866","url":null,"abstract":"<p><p><b>Rationale:</b> Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a critical syndrome with a mortality rate of up to 40%, and it is characterized by a prominent inflammatory cascade. The inflammasome and pyroptosis play crucial regulatory roles in regulating various inflammatory-related diseases by serving as pivotal signaling platforms for inflammatory responses and mediating the release of substantial quantities of inflammatory factors. Our previous studies confirmed that GC-1, a clinical-stage thyroid hormone analog, effectively mitigated pulmonary fibrosis by restoring mitochondrial function in epithelial cells. However, the potential effects of GC-1 on macrophage inflammasome assembly and pyroptosis in lung injury as well as the underlying mechanisms, remain unclear. <b>Methods:</b> The effects of GC-1 on lung injury, oxidative damage and inflammation were evaluated in two murine models of ALI (LPS- or HCl-induced models) by assessing lung pathology, the concentrations of IL-1β and IL-18 in BAL fluid, inflammasome and the levels of inflammasome- and pyroptosis-related proteins. Additionally, the impact of GC-1 on ROS-mediated inflammasome assembly and pyroptosis was investigated by examining ROS levels, Nrf2 signaling, and inflammasome adaptor protein ASC levels in mouse alveolar macrophages and human THP-1 macrophages treated with LPS and ATP. The Nrf2 inhibitor ML385 and the mitochondrial-ROS inhibitor Mito-TEMPO were used to further elucidate the effect of GC-1 on the Nrf2-p53-ASC pathway. <b>Results:</b> GC-1 significantly alleviated inflammation and lung injury in ALI model mice, as indicated by pulmonary pathology, inflammatory cytokine levels, ROS production and pyroptosis rates. Consistently, GC-1 inhibited ASC recruitment and oligomerization in macrophages, which suppressed the gasdermin D-mediated release of IL-1β and IL-18. These findings indicated a reduction in inflammasome assembly and pyroptosis initiation. Further research revealed that GC-1 may mitigate oxidative stress induced by mitochondrial damage through Nrf2 signaling, thereby inhibiting the expression of ROS-activated p53 and the target gene ASC. This protective effect of GC-1 could be reversed by ML385 and mimicked by Mito-TEMPO. <b>Conclusions:</b> This study presents a novel mechanism for treating ALI in which GC-1 inhibits macrophage ROS-mediated inflammasome assembly and pyroptosis through Nrf2-p53-ASC pathway. These findings highlight the promising potential of the use of GC-1 as an anti-inflammatory and antioxidant drug in the treatment of ALI/ARDS.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2360-2374"},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483928","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":"Poly (I:C)-induced inflammation requires the activation of toll-like receptor 3/Ca²⁺/CaMKII/pannexin 1-dependent signaling.","authors":"Magdiel Salgado, Vania Sepúlveda-Arriagada, Macarena Konar-Nié, María A García-Robles, Juan C Sáez","doi":"10.7150/thno.100687","DOIUrl":"10.7150/thno.100687","url":null,"abstract":"<p><p>Pannexin1 (Panx1) is a glycoprotein, ubiquitously expressed throughout vertebrate tissues. In the cell membrane, it forms non-selective hemichannels (Panx1 HCs) that allow the release of ATP. This extracellular ATP triggers purinergic signaling relevant to the immune responses to pathogens, including viruses. While the activity of Panx1 HCs is known to be elevated by some viruses, the underlying molecular mechanism remains elusive. <b>Methods</b>: In this study, we used Poly(I:C), a double-stranded RNA analog that constitutes a hallmark of viral infections. Peritoneal macrophages were obtained from wild-type and Panx1 knock-out mice. The mRNA levels of proinflammatory cytokines were quantified by RT-qPCR. We also evaluated hemichannel activity through dye uptake assays, whereas Ca²⁺ signals were studied using Fura-2 and GcamP6. Panx1-P2X₇R interaction was studied by proximity ligation assays. <b>Results:</b> Panx1 expression and activity were crucial for the proinflammatory response induced by Poly(I:C) in RAW264.7 cells and peritoneal macrophages. In HeLa cells transfected with mPanx1 (HeLa-mPanx1) and RAW264.7 cells, Poly (I:C) increased Panx1 HC activity in a concentration-dependent manner, which was inhibited by ¹⁰Panx1, a peptide that selectively blocks Panx1 HCs. Furthermore, the Poly(I:C)-induced rise in Panx1 HC activity correlated with a rapid increase in intracellular Ca²⁺ signal, dependent on TLR3 and P2X₇R activity. Interestingly, lasting exposure to Poly (I:C) promoted the interaction and internalization of the Panx1-P2X₇R complex, which depended on CaMKII, Panx1 HC, and P2X₇R activities. The Poly (I:C)-induced increase in Panx1 HC activity was entirely prevented by Ca²⁺ chelation with BAPTA-AM, CaMKII blockage with KN-62, or PKA activation with db-cAMP. These findings were consistent with data from Panx1 mutants that either avoid or mimic phosphorylation at kinase target sites. Supporting this finding, we demonstrated that CaMKII activity is essential for the inflammatory response triggered by Poly (I:C) in macrophages. <b>Conclusion</b>: A TLR3/Ca²⁺/CaMKII/Panx1 HC pathway is crucial in orchestrating the cellular response to viral patterns and presents a potential novel target for preventing infections and alleviating the harmful effects associated with RNA-based viral infections.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2470-2486"},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483981","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":"Renal tubular epithelial-derived follistatin-like 1 protects against UUO-induced renal fibrosis in mice via inhibiting NF-κB-mediated epithelial inflammation.","authors":"Zhuan Niu, Jiasen Guo, Xingzu Liu, Mo Chen, Yueyue Jin, Maolin Yao, Xiaoxu Li, Qianqian Che, Shuzi Li, Chenjie Zhang, Kunyue Shangguan, Dekun Wang, Chuan'ai Chen, Wenli Yu, Xiaoyue Tan, Wen Ning, Lian Li","doi":"10.7150/thno.100969","DOIUrl":"10.7150/thno.100969","url":null,"abstract":"<p><p><b>Rationale:</b> Renal fibrosis is commonly recognized as the ultimate pathway for most chronic kidney diseases (CKD). Renal tubular epithelial inflammation drives the initiation and progression of renal fibrosis. Follistatin-like 1 (FSTL1) is a small matricellular protein, whose expression pattern, function and underlying mechanism in regulating renal inflammation and fibrosis remains largely unknown. <b>Methods:</b> We utilized two <i>Fstl1</i>-deficient genetic mouse models: heterozygous <i>Fstl1^+/-</i> mice and whole-body <i>Fstl1</i> conditional knockout mice, and a mouse model with FSTL1 overexpression via adenoviral vector infection. These mice were subjected to unilateral ureteral obstruction (UUO). We used an <i>Fstl1</i> lineage tracing mouse to investigate the expression and location of induced FSTL1 in the obstructed kidney. We investigated the effect of FSTL1 on TNF-α induced epithelial inflammation and the NF-κB pathway by overexpression or knockdown of FSTL1 in human kidney epithelial cells (HK2). <b>Results:</b> We observed increased expression of FSTL1 in kidneys from patients with CKD, and UUO mouse model of renal injury and fibrosis. Deletion of <i>Fstl1</i> in mice aggravated UUO-induced inflammatory kidney injury and subsequent fibrosis. Conversely, overexpression of FSTL1 by adenoviral vector infection in mice mitigated expression of proinflammatory cytokines and the fibrotic phenotype. Mechanistically, we identified that increased FSTL1 was mostly derived from the tubular epithelium of the obstructed mouse kidney. FSTL1 inhibited human renal epithelial cell inflammatory responses, as assessed by reducing the NF-κB pathway, release of IL-1β and IL-6, expression of intercellular adhesion molecule 1 (ICAM-1), and monocyte adhesion to kidney epithelial cells. <b>Conclusions:</b> These findings suggest that FSTL1 plays a protective role against kidney fibrosis by inhibiting renal epithelial inflammation via the NF-κB pathway in epithelium, thereby offering a potential novel strategy for treating progressive CKD.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2413-2427"},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483982","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":"The sentinel against brain injury post-subarachnoid hemorrhage: efferocytosis of erythrocytes by leptomeningeal lymphatic endothelial cells.","authors":"Hong-Ji Deng, Yun-Huo Xu, Kun Wu, Yun-Cong Li, Yong-Jin Zhang, Han-Fu Yu, Chong Li, Dan Xu, Fei Wang","doi":"10.7150/thno.103701","DOIUrl":"10.7150/thno.103701","url":null,"abstract":"<p><p><b>Rationale:</b> The clearance of extravasated erythrocytes represents the most reasonable strategy against brain injury post-subarachnoid hemorrhage (SAH). There is little knowledge about the autologous clearance of extravasated erythrocytes post-SAH. The leptomeningeal lymphatic endothelial cells (LLECs) have been less studied functionally, which were firstly harvested and cultured <i>in vitro</i> by our group previously and are probably related to the clearance of extravasated erythrocytes post-SAH for they closely surround subarachnoid space. <b>Methods:</b> We established a SAH animal model, employed primary LLECs <i>in vitro</i>, mimicked the conditions of the SAH <i>in vitro</i>, performed RNA sequencing, and transfected LLECs with adenovirus and adeno-associated virus both <i>in vivo</i> and <i>in vitro</i> to reveal the molecular mechanisms of efferocytosis of erythrocytes by LLECs and its neuroprotection post-SAH. <b>Results:</b> Firstly, we demonstrated the eryptosis-initiated degradation of extravasated erythrocytes <i>in vitro</i>. Furthermore, we found LLECs preferentially adhered and engulfed apoptotic erythrocytes <i>in vivo</i> and <i>in vitro</i> while sparing from intact erythrocytes, suggesting their novel capacity in the efferocytosis of erythrocytes. Additionally, the efferocytosis of erythrocytes by LLECs plays a role on neuroprotection via improving neurological functions, maintaining neurostructural integrity, and alleviating neuropathological consequences post-SAH. During efferocytosis, phosphatidylserine (PS) and phosphatidylserine receptor (PSR) mediated the recognition of apoptotic erythrocytes by LLECs. We also confirmed that NHL repeat-containing 2 (NHLRC2) positively regulated the efferocytosis of erythrocytes by LLECs to serve as a central regulator in it mediated neuroprotection post-SAH. <b>Conclusions:</b> This study elucidated the efferocytosis of erythrocytes by LLECs and subsequently neuroprotection post-SAH. These findings highlight a prompt, efficient, and regulable pathway for the autologous clearance of extravasated erythrocytes that performs as a sentinel against brain injury post-SAH.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2487-2509"},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483985","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":"Nsun2 controls cardiac homeostasis and hypertrophic response by regulating PRKACA expression.","authors":"Dongdong Jian, Xiaolei Cheng, Datun Qi, Shixing Wang, Chenqiu Wang, Yingchao Shi, Zhen Li, Shouyi Jin, Zhen Jia, Peng Teng, Zhen Pei, Xiaoping Gu, Liguo Jian, Wengong Wang, Xia Yi, Junyue Xing, Hao Tang","doi":"10.7150/thno.104441","DOIUrl":"10.7150/thno.104441","url":null,"abstract":"<p><p><b>Rationale:</b> Internal modifications of mammalian RNA have been suggested to be essential for the maintenance of cardiac homeostasis. However, the role of RNA cytosine methylation (m5C) in the heart remains largely unknown. <b>Methods:</b> Bulk and single cell RNA sequencing data and tissues from the human hearts were exploited for analyzing the expression of RNA m5C modifying proteins. Neonatal rat and adult mouse cardiomyocytes were isolated to assess the impact of Nsun2 on cellular hypertrophic response. Cre/LoxP-mediated gene knockout and recombinant adeno-associated virus serotype 9 (rAAV9) were employed respectively to achieve cardiac-specific interference of the expression of related genes in mice that were subjected to heart stresses from aging, aortic constriction, and angiotensin II stimulation. RNA m5C immunoprecipitation sequencing (m5C-RIP-seq), RNA pull-down, polysome profiling, reporter gene analysis, and IonOptix measurement were conducted to elucidate the involved regulatory mechanisms. <b>Results:</b> Nsun2 expression was significantly elevated in human, rat, and mouse hypertrophic myocardial cells. Knockout of Nsun2 (αMHC-Cre^ERT2, Nsun2 flox^+/+) abolished the hypertrophic response of mice to diverse stresses, while accelerating the progression of heart failure. Mechanistically, Nsun2 specifically methylates PKA catalytic subunit alpha (PRKACA) mRNA, which substantially promotes PRKACA translation in a YBX1-dependent manner. Nsun2 ablation markedly attenuated the activation of PKA signaling, as evidenced by the reduced PKA activity and protein phosphorylation levels of PKA substrates, impaired myocyte contraction and relaxation, and disturbed calcium transients. Overexpressing Nsun2 and PRKACA-3'UTR transcripts in the myocardia sensitized and desensitized heart hypertrophic responses, respectively, whereas co-administration of the PKA inhibitor H-89 or overexpressing PRKACA-3'UTR transcript lacking Nsun2 methylating regions failed to produce corresponding responses, reiterating the significance of Nsun2-PRKACA regulation in the cardiac hypertrophic program. <b>Conclusion:</b> These observations reveal the importance of Nsun2-PRKACA regulation in cardiac homeostasis, which provides novel insights into heart function modulation and sheds light on future treatments for hypertrophic remodeling associated heart diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2393-2412"},"PeriodicalIF":12.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483848","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":"Targeted delivery of Grem1 and IL-10 separately by mesenchymal stem cells effectively mitigates SETD2-deficient inflammatory bowel disease.","authors":"Rebiguli Aji, Yue Xu, Ziyi Wang, Wenxin Feng, Liming Gui, Hanyu Rao, Wei Zhang, Ningyuan Liu, Wei-Qiang Gao, Li Li","doi":"10.7150/thno.105876","DOIUrl":"10.7150/thno.105876","url":null,"abstract":"<p><p><b>Rationale:</b> Inflammatory bowel disease (IBD) is a relapsing and idiopathic disorder. The low therapeutic efficacy of IBD urgently prompts us to seek new treatment methods. <b>Methods and Results:</b> In this study, we report an adipose-derived mesenchymal stem cell (AT-MSC)-based treatment strategy in which AT-MSCs specifically deliver BMP inhibitor Grem1 and anti-inflammatory factor IL-10 to inflammatory colon tissues in SETD2 deficient dextran sulfate sodium (DSS)-induced colitis mouse models. Targeted delivery of Grem1 reduced colitis by promoting intestinal stem cell regeneration and enhancing mucosal regenerative capacity. Furthermore, targeted delivery of IL-10 reduced colitis by reducing inflammatory cytokines. <b>Conclusion:</b> Our AT-MSCs based therapeutic strategy effectively mitigated IBD. This study has deepened our understanding of IBD therapy and provided a theoretical foundation for its clinical treatment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2215-2228"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483984","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":"USP14 modulates stem-like properties, tumorigenicity, and radiotherapy resistance in glioblastoma stem cells through stabilization of MST4-phosphorylated ALKBH5.","authors":"Xiao Zhou, Qiaoxi Xia, Botao Wang, Junjun Li, Bing Liu, Sisi Wang, Min Huang, Ronghui Zhong, Shi-Yuan Cheng, Xuan Wang, Xiaobing Jiang, Tianzhi Huang","doi":"10.7150/thno.103629","DOIUrl":"10.7150/thno.103629","url":null,"abstract":"<p><p><b>Rationale</b>: Glioblastoma (GBM) is the most aggressive type of primary brain cancer and contains self-renewing GBM stem cells (GSCs) that contribute to tumor growth and therapeutic resistance. However, molecular determinants governing therapeutic resistance of GSCs are poorly understood. <b>Methods</b>: We performed genome-wide analysis of deubiquitylating enzymes (DUBs) in patient-derived GSCs and used gene-specific shRNAs to identify an important DUB gene contributing to GSC survival and radioresistance. Subsequently, we employed mass spectrometry and immunoprecipitation to show the interaction between USP14 and ALKBH5, and identified the upstream kinase MST4, which is essential for the deubiquitylation and stabilization of ALKBH5. Additionally, we performed integrated transcriptome and m⁶A-seq analyses to uncover the key downstream pathways of ALKBH5 that influence GSC radioresistance. <b>Results</b>: Our study demonstrates the essential role of the deubiquitinase USP14 in maintaining the stemness, tumorigenic potential, and radioresistance of GSCs. USP14 stabilizes the m⁶A demethylase ALKBH5 by preventing its K48-linked ubiquitination and degradation through HECW2. The phosphorylation of ALKBH5 at serine 64 and 69 by MST4 increases its interaction with USP14, promoting ALKBH5 deubiquitylation. Furthermore, ALKBH5 directly interacts with the USP14 transcript in a manner dependent on YTHDF2, establishing a positive feedback loop that sustains the overexpression of both proteins in GSCs. The MST4-USP14-ALKBH5 signaling pathway is crucial for enhancing stem cell-like traits, facilitating homologous recombination repair of DNA double-strand breaks, and promoting radioresistance and tumorigenicity in GSCs. This signaling cascade is further stimulated in GSCs following exposure to ionizing radiation (IR). Inhibiting USP14 with the small molecule IU1 disrupts ALKBH5 deubiquitylation and increases the effectiveness of IR therapy on GSC-derived brain tumor xenografts. <b>Conclusion:</b> Our results identify the MST4-USP14-ALKBH5 signaling pathway as a promising therapeutic target for treating GBM.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2293-2314"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484004","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":"3D bioprintable Mg²⁺-incorporated hydrogels tailored for regeneration of volumetric muscle loss.","authors":"Moon Sung Kang, Jeong Min Kim, Hyo Jung Jo, Hye Jin Heo, Yun Hak Kim, Kyung Min Park, Dong-Wook Han","doi":"10.7150/thno.103677","DOIUrl":"10.7150/thno.103677","url":null,"abstract":"<p><p><b>Rationale:</b> Current therapeutic approaches for volumetric muscle loss (VML) face challenges owing to limited graft availability and insufficient bioactivity. Three-dimensional (3D) bioprinting has become an alternative technology for fabricating native tissue-mimetic grafts, allowing for tailored structures and complex designs. <b>Methods:</b> We developed an Mg²⁺-incorporated bioink composed of thiolated gelatin (GtnSH) and maleimide-conjugated gelatin (GtnMI) decorated with magnesium peroxide (MgO₂), referred to as a GtnSH/GtnMI/MgO₂ bioink. We designed <i>in situ</i> crosslinking between GtnSH and GtnMI to prepare cytocompatible bioink for 3D bioprinting of muscle mimetics. <b>Results:</b> The incorporated MgO₂ particles provided oxygen supplementation and myogenic cues. <i>In vitro</i> assays demonstrated that C2C12 myoblasts encapsulated in the GtnSH/GtnMI/MgO₂ bioink exhibited high viability, intrinsic proliferation rate, and increased expression of key myogenic markers. <i>In vivo</i> transplantation of the 3D bioprinted GtnSH/GtnMI/MgO₂ constructs facilitated muscle mass restoration and M2 macrophage polarization. Additionally, they downregulate the activities of CD4⁺ and CD8⁺ lymphocytes, inducing a transition from the initial inflammatory to the restoration phase. <b>Conclusion:</b> The GtnSH/GtnMI/MgO₂ bioink is a potential therapeutic strategy for enhancing myogenesis and skeletal muscle tissue regeneration.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2185-2200"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483524","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}