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Cyclic mechanical stretching enhances mitophagy and oxidative stress resistance in adipose-derived stem cells via the Piezo1/ATP axis to accelerate wound healing. 循环机械拉伸通过Piezo1/ATP轴增强脂肪来源干细胞的线粒体自噬和氧化应激抵抗,加速伤口愈合。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-09-08 eCollection Date: 2025-01-01 DOI: 10.7150/thno.118364
Yujie Xiao, Zhijun Shi, Yixuan Yuan, Danna Yao, Rongqin Feng, Yue Zhang, Deli Zhao, Hao Zhang, Panpan Sun, Yang Liu, Yan Li, Xuefeng Shen, Zhantong Wang, Dahai Hu, Hao Guan, Hongtao Wang
{"title":"Cyclic mechanical stretching enhances mitophagy and oxidative stress resistance in adipose-derived stem cells via the Piezo1/ATP axis to accelerate wound healing.","authors":"Yujie Xiao, Zhijun Shi, Yixuan Yuan, Danna Yao, Rongqin Feng, Yue Zhang, Deli Zhao, Hao Zhang, Panpan Sun, Yang Liu, Yan Li, Xuefeng Shen, Zhantong Wang, Dahai Hu, Hao Guan, Hongtao Wang","doi":"10.7150/thno.118364","DOIUrl":"10.7150/thno.118364","url":null,"abstract":"<p><p>Adipose-derived stem cells (ADSCs) hold significant potential in regenerative medicine, yet their therapeutic efficacy is often limited by low survival rates in the presence of oxidative stress. While mechanical cues regulate cytoskeletal dynamics, their roles in modulating cellular metabolism and mitochondrial adaptation remain unexplored. This study aimed to elucidate how physiological-range cyclic mechanical stretching (CMS) enhances ADSCs resistance to oxidative stress through the Piezo1/ATP signaling axis, thereby establishing an innovative strategy for developing antioxidant-functionalized stem cell therapies. <b>Methods:</b> To examine the impact of CMS on oxidative stress resistance, ADSCs were exposed to CMS (8% strain, 0.5 Hz, 24 h) using the Flexcell FX-6000 system. Oxidative stress models employed H₂O₂ (200 μM), with apoptosis, mitochondrial function, and metabolic flux analyzed <i>in vitro</i>. A murine full-thickness wound model was used to assess <i>in vivo</i> survival and regenerative outcomes. <b>Results:</b> CMS activated Piezo1 channels, resulting in enhanced ATP synthesis and remodeling of the tricarboxylic acid cycle. This improved the effectiveness of mitochondrial oxidative phosphorylation. Mechanically preconditioned ADSCs exhibited reduced apoptosis, ​enhanced oxidation resistance, stabilized mitochondrial membrane potential, and upregulated mitophagy. <i>In vivo</i>, these cells demonstrated superior healing capacity and accelerated wound closure. <b>Conclusion:</b> CMS orchestrated the Piezo1/ATP-driven metabolic-mitochondrial axis to enhance ADSCs oxidative stress resistance by coupling metabolic reprogramming with mitophagy activation. This mechanometabolic interaction identifies mechanical signaling as a direct regulator of cellular bioenergetics, offering a translatable strategy to engineer antioxidant-functionalized stem cells for regenerative therapies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9862-9884"},"PeriodicalIF":13.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213613","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}
引用次数: 0
Endothelial cell-derived SDF-1α elicits stemness traits of glioblastoma via dual-regulation of GLI1. 内皮细胞源性SDF-1α通过双调控GLI1诱导胶质母细胞瘤的干性特征。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-09-08 eCollection Date: 2025-01-01 DOI: 10.7150/thno.108843
Ye Yuan, Xudong Liu, Liwen Kuang, Shixue Yang, Lihong Wang, Jiao Wang, Sen Wei, Zexuan Yan, Qinghua Ma, Juan Lei, Yu Zhou, Yu Chen, Jiongming Chen, Tao Luo, Kaidi Yang, Mengsi Zhang, Yongsheng Li
{"title":"Endothelial cell-derived SDF-1α elicits stemness traits of glioblastoma <i>via</i> dual-regulation of GLI1.","authors":"Ye Yuan, Xudong Liu, Liwen Kuang, Shixue Yang, Lihong Wang, Jiao Wang, Sen Wei, Zexuan Yan, Qinghua Ma, Juan Lei, Yu Zhou, Yu Chen, Jiongming Chen, Tao Luo, Kaidi Yang, Mengsi Zhang, Yongsheng Li","doi":"10.7150/thno.108843","DOIUrl":"10.7150/thno.108843","url":null,"abstract":"<p><p><b>Background:</b> Glioma stem cells (GSCs) play a critical role in the poor treatment outcomes observed in glioblastoma (GBM) patients. A primary focus of current glioma research is understanding the maintenance of stemness in GSCs and their interactions with the tumor microenvironment. In GBMs, the perivascular niche serves as a protective environment for GSCs, contributing to tumor recurrence. However, the molecular mechanisms that sustain this reservoir remain poorly understood. <b>Methods:</b> The analysis of single-cell transcriptional data in GBM was conducted to identify signaling pathways in endothelial cells (ECs) that promote stemness traits in glioma cells. Histological staining and the IvyGAP dataset were utilized to evaluate the anatomical microenvironment of glioma. The molecular mechanisms underlying the maintenance of stemness in GSCs, influenced by ECs, were assessed using ELISA, Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), in vivo ubiquitination assays, and other molecular biology experiments. An orthotopic xenograft model was employed to examine the stemness phenotype of GBM cells in the presence of ECs, as well as the synergistic effects of GSK690693 and AMD3100 in inhibiting GBM cells. <b>Results:</b> We found that GSCs are located in close proximity to microvessels, and we identified the CXCL12-CXCR4 signaling pathway in ECs as a promoter of stemness traits in glioma cells. GBM cells can transition to a stem-like state in response to stromal cell-derived factor-1α (SDF-1α) secreted by ECs. This transition activates the CXCR4-mediated AKT/NF-κB signaling pathway, leading to the subsequent upregulation of glioma-associated oncogene homolog 1 (GLI1), a key transcription factor for maintaining stemness. Furthermore, we discovered that SDF-1α influences the turnover of GLI1 protein in GBM cells by modulating GLI1-associated polyubiquitin chains through the phosphorylation of the deubiquitinase USP28 at serine 67. This modification enhances the stemness-maintaining properties of GLI1 via both transcriptional regulation and protein quality control mechanisms. Preclinical studies indicated that the combination of the CXCR4 antagonist AMD3100 and the AKT inhibitor GSK690693 synergistically inhibits GBM cell progression. <b>Conclusions:</b> Our findings unveil a novel signaling axis between ECs and tumor cells that directly impacts the acquisition of stemness traits, suggesting that targeting this pathway could represent a promising therapeutic strategy against GBM.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9819-9837"},"PeriodicalIF":13.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213689","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}
引用次数: 0
Kazald1 attenuates chondrocyte fibrosis to potentiate hyaline cartilage regeneration by interfering with the pro-fibrotic TGF-β signaling. Kazald1通过干扰促纤维化TGF-β信号通路,减弱软骨细胞纤维化,促进透明软骨再生。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-09-08 eCollection Date: 2025-01-01 DOI: 10.7150/thno.113604
Yue Zhu, Haoyang Liu, Yuting Zhang, Danning Zheng, Yaning Li, Jialin Chen, Jiake Xu, Wei Zhang
{"title":"Kazald1 attenuates chondrocyte fibrosis to potentiate hyaline cartilage regeneration by interfering with the pro-fibrotic TGF-β signaling.","authors":"Yue Zhu, Haoyang Liu, Yuting Zhang, Danning Zheng, Yaning Li, Jialin Chen, Jiake Xu, Wei Zhang","doi":"10.7150/thno.113604","DOIUrl":"10.7150/thno.113604","url":null,"abstract":"<p><p><b>Background:</b> Cartilage regeneration remained a significant challenge, often leading to the formation of mechanically inferior fibrocartilage instead of physiological hyaline cartilage. Currently, there were no effective treatments for cartilage fibrosis, necessitating the exploration of potential molecular targets. <b>Methods:</b> We perform single-cell sequencing of rat spontaneously formed fibrocartilage following osteochondral injury and rat normal hyaline cartilage with a comprehensive analysis of the heterogeneous cell subpopulations between two groups. Subsequently, we express and purify the full length of recombinant human Kazald1 protein (aa 31-304) with predicted tertiary and secondary structures, and determine its anti-fibrotic effect and explore its regulatory mechanisms using in vitro cultured chondrocytes, in the presence or absence of the pro-fibrotic factor TGF-β1. Finally, we evaluate the therapeutic potential of recombinant Kazald1 protein in promoting hyaline cartilage regeneration and maintenance using rat osteochondral injury models and human cartilage explants, respectively. <b>Results:</b> Through single cell sequencing of hyaline cartilage and fibrocartilage, we identified Kazald1 as a key molecule in maintaining cartilage homeostasis. During cartilage fibrosis, Kazald1 expression was significantly down-regulated and becomes imbalanced with TGF-β1. Recombinant Kazald1 protein effectively inhibited TGF-β1-induced chondrocyte fibrosis and preserves chondrocyte phenotype. Mechanistically, Kazald1 formed a dimer with TGFBR1, blocking the pro-fibrotic TGF-β1-Akt/Smad3 signaling and suppressing the expression of fibrotic genes. In rat models of cartilage injuries, the combination of Kazald1 and TGF-β1 effectively promoted hyaline cartilage regeneration with structural restoration and functional recovery. This combination also enhanced hyaline cartilage maintenance and inhibited TGF-β1-induced cartilage fibrosis in human cartilage explants. <b>Conclusion:</b> This study unveils the pivotal role of Kazald1 in the regulation of cartilage fibrosis and highlights its potential as a therapeutic agent for facilitating hyaline cartilage regeneration.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9885-9910"},"PeriodicalIF":13.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213716","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}
引用次数: 0
Naturally derived hydrogel with antioxidant, angiogenesis and photothermal effect to accelerate infected diabetic wound healing and reduce scar formation. 天然来源的水凝胶,具有抗氧化,血管生成和光热效应,加速感染糖尿病伤口愈合,减少疤痕形成。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-09-08 eCollection Date: 2025-01-01 DOI: 10.7150/thno.117179
Mengyu Yang, Pengyuan Liu, Pei Cheng, Chenghao Li, Jingmei Liu, Haifeng Sun, Fangxia Guan, Minghao Yao
{"title":"Naturally derived hydrogel with antioxidant, angiogenesis and photothermal effect to accelerate infected diabetic wound healing and reduce scar formation.","authors":"Mengyu Yang, Pengyuan Liu, Pei Cheng, Chenghao Li, Jingmei Liu, Haifeng Sun, Fangxia Guan, Minghao Yao","doi":"10.7150/thno.117179","DOIUrl":"10.7150/thno.117179","url":null,"abstract":"<p><p><b>Rationale:</b> Diabetic wound treatment remains a central issue in global healthcare due to the unitary nature of clinical dressings, which lack systemic multifunctionality in terms of tissue adhesion, shape adaptation, hemostasis, antioxidant, anti-inflammatory and antimicrobial abilities and promotion of tissue repair. <b>Methods:</b> A hydrogel dressing loaded with active molecules of traditional Chinese medicine has been developed for the treatment of infected diabetic wounds. The naturally derived multifunctional hydrogel dressing (abbreviated as CTP) composed of Carboxymethyl chitosan (CMCS), 3,4,5-Trihydroxybenzaldehyde (THBA), and Phlorizin (PHL) was fabricated by a simple mixing process avoiding the use of any additional cross-linking agents or functional modifications. <b>Results:</b> The developed hydrogel demonstrated adhesiveness, shape adaptability, swelling, photothermal responsiveness, and other desirable biological functions, including hemostatic behavior and antibacterial, antioxidant and proangiogenic activities. In a diabetic wound model, compared with Hydrosorb Gel (a commercial hydrogel wound dressing), the CTP hydrogel in combination with NIR treatment accelerated diabetic wound healing by effectively preventing infection, decreasing inflammatory response, promoting re-epithelialization, enhancing both regeneration of skin attachments (e.g., hair follicles) and deposition of collagen. It also reduced scar formation and improved the overall healing process. <b>Conclusions:</b> As a functional wound dressing, CTP hydrogel shows great promise in diabetic wound repair.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9838-9861"},"PeriodicalIF":13.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213645","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}
引用次数: 0
The pathophysiology of mixed Alzheimer's disease and vascular dementia. 混合性阿尔茨海默病与血管性痴呆的病理生理学研究。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-09-03 eCollection Date: 2025-01-01 DOI: 10.7150/thno.118737
Mutaz Sarhan, Christian Wohlfeld, Ariel Perry-Mills, Jeffrey Meyers, James Fadel, E Angela Murphy, Leonardo Bonilha, Daping Fan
{"title":"The pathophysiology of mixed Alzheimer's disease and vascular dementia.","authors":"Mutaz Sarhan, Christian Wohlfeld, Ariel Perry-Mills, Jeffrey Meyers, James Fadel, E Angela Murphy, Leonardo Bonilha, Daping Fan","doi":"10.7150/thno.118737","DOIUrl":"10.7150/thno.118737","url":null,"abstract":"<p><p>Mixed dementia is caused most often by the coexistence of Alzheimer's disease (AD) and vascular dementia (VaD) pathologies. This disease presents challenges due to its complex, dual pathology. In this review, we summarize the current understanding of the pathophysiology of AD and VaD, with a particular emphasis on vascular factors that accelerate or exacerbate AD pathology. We then describe animal models, in vitro cell culture systems, and brain organoid models that have been developed or are currently being developed to elucidate the neurodegenerative and vascular components of MD. This review provides an evaluation of the panorama of factors that influence MD pathophysiology and how basic science models can incorporate these factors to advance the knowledge related to the mechanisms of the disease and guide the screening of novel therapeutic approaches.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9793-9818"},"PeriodicalIF":13.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213576","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}
引用次数: 0
Enhancing glymphatic transport through angiotensin II type 2 receptor activation promotes neurological recovery after traumatic brain injury. 通过激活血管紧张素II型2受体增强淋巴转运促进创伤性脑损伤后神经系统恢复。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-09-03 eCollection Date: 2025-01-01 DOI: 10.7150/thno.117743
Xiaoyu Zhang, Bin Sun, Wenzhong Li, Tianyi Liu, Wenchen Li, Bo Chen, Chuan He, Qin Liu, Shoujun Zhu, Haifeng Wang
{"title":"Enhancing glymphatic transport through angiotensin II type 2 receptor activation promotes neurological recovery after traumatic brain injury.","authors":"Xiaoyu Zhang, Bin Sun, Wenzhong Li, Tianyi Liu, Wenchen Li, Bo Chen, Chuan He, Qin Liu, Shoujun Zhu, Haifeng Wang","doi":"10.7150/thno.117743","DOIUrl":"10.7150/thno.117743","url":null,"abstract":"<p><p><b>Background:</b> Traumatic brain injury (TBI) may impair the function of the glymphatic system, leading to diminished metabolic waste clearance and aggravated neurological deficits. While angiotensin II type 2 receptor (AT2R) activation has demonstrated neuroprotective effects, its specific impact on the glymphatic system following TBI remains uncharacterized. <b>Methods:</b> We utilized near-infrared II (NIR-II) probes with distinct protein-binding capacities to visualize glymphatic transport in TBI mice and investigate how compound 21 (C21)-mediated AT2R activation modulates post-traumatic glymphatic function. Perivascular aquaporin-4 (AQP4) polarization was analyzed by immunofluorescence. RNA sequencing was performed to explore the C21-induced dynamic immune modulation. β-amyloid clearance efficiency and phosphorylated tau accumulation were quantified in mouse brain tissue. Motor and cognitive functions were comprehensively evaluated through standardized behavioral tests. <b>Results:</b> Our results demonstrate that C21-mediated AT2R activation enhanced glymphatic influx and promoted glymphatic clearance after TBI. Mechanistically, AT2R activation restored perivascular aquaporin-4 (AQP4) polarization and cerebral blood flow, suppressed astrogliosis and microglial activation, and attenuated neuroinflammatory responses. Furthermore, AT2R activation enhanced β-amyloid clearance efficiency and reduced phosphorylated tau accumulation, thereby promoting motor and cognitive functional recovery. <b>Conclusion:</b> By employing non-invasive or minimally invasive NIR-II imaging, our study highlights the protective effects of AT2R activation on the glymphatic system following TBI, revealing its potential as a promising therapeutic strategy for mitigating TBI-induced damage and improving neurological outcomes.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9775-9792"},"PeriodicalIF":13.3,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213764","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}
引用次数: 0
Machine learning-enhanced confocal Raman imaging enables label-free diagnosis and spatial metabolic profiling of isoniazid-induced hepatotoxicity. 机器学习增强的共聚焦拉曼成像能够对异烟肼引起的肝毒性进行无标记诊断和空间代谢分析。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI: 10.7150/thno.119785
Shimei Wang, Xiaoren Wang, Xudong Cui, Xiaotong Xie, Zhu Zhu, Tomii Ayaka, Renxing Song, Liping Zhou, Jin Sun, Li Zhang, Ruisheng Ge, Lei Yu, Yang Li
{"title":"Machine learning-enhanced confocal Raman imaging enables label-free diagnosis and spatial metabolic profiling of isoniazid-induced hepatotoxicity.","authors":"Shimei Wang, Xiaoren Wang, Xudong Cui, Xiaotong Xie, Zhu Zhu, Tomii Ayaka, Renxing Song, Liping Zhou, Jin Sun, Li Zhang, Ruisheng Ge, Lei Yu, Yang Li","doi":"10.7150/thno.119785","DOIUrl":"10.7150/thno.119785","url":null,"abstract":"<p><p><b>Rationale:</b> Isoniazid-induced liver injury (INH-ILI) poses a significant clinical challenge due to the lack of reliable, non-invasive, and real-time diagnostic tools. Here, we present an integrated platform that combines label-free confocal Raman spectroscopy imaging, machine learning (ML), and targeted metabolomics to identify and classify INH-ILI in a murine model. <b>Methods:</b> An INH-ILI mouse model was established, and Raman imaging and subsequent data analysis were performed on the control and INH-ILI at 7, 14, 21, and 28-day groups. Alterations in hepatic metabolites following INH-ILI were elucidated. Furthermore, ML techniques were employed to identify subtle differences between the control and INH-ILI groups. <b>Results:</b> Distinct Raman spectral shifts, notably the emergence of a 1638 cm<sup>-1</sup> peak in injured liver tissues compared to characteristic peaks at 1203, 1266, and 1746 cm<sup>-1</sup> in controls, were observed. ML models including support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and convolutional neural network (CNN) have achieved accurate staging and classification of INH-ILI (AUC > 0.95). Metabolomic analysis further confirmed disruptions in lipid and aromatic amino acid metabolism, particularly involving phenylalanine-tyrosine imbalance linked to oxidative stress. <b>Conclusions:</b> This method enables precise, high-throughput, and spatially resolved diagnosis of INH-ILI, with strong potential for clinical translation in drug-induced liver injury assessment.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9663-9677"},"PeriodicalIF":13.3,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213699","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}
引用次数: 0
Transcriptomic Profiling of the Tumor Immune Microenvironment Reveals Prognostic Markers in mCRPC Patients Treated with LuPSMA Therapy. 肿瘤免疫微环境的转录组学分析揭示了接受LuPSMA治疗的mCRPC患者的预后标志物。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI: 10.7150/thno.113614
Analena Handke, Leonor Lopes, Claudia Kesch, Christopher Darr, Elai Davicioni, Kuangyu Shi, Tugce Telli, Wolfgang P Fendler, Ken Herrmann, Katharina Lückerath, Boris Hadaschik, Robert Seifert
{"title":"Transcriptomic Profiling of the Tumor Immune Microenvironment Reveals Prognostic Markers in mCRPC Patients Treated with LuPSMA Therapy.","authors":"Analena Handke, Leonor Lopes, Claudia Kesch, Christopher Darr, Elai Davicioni, Kuangyu Shi, Tugce Telli, Wolfgang P Fendler, Ken Herrmann, Katharina Lückerath, Boris Hadaschik, Robert Seifert","doi":"10.7150/thno.113614","DOIUrl":"10.7150/thno.113614","url":null,"abstract":"<p><p><b>Rationale:</b> The mode of action of [<sup>177</sup>Lu]Lu-PSMA-617 (LuPSMA) therapy is not fully understood and a relevant fraction of patients show treatment failure. Therefore, this study aimed to investigate the prognostic significance of immune suppression in the tumor immune microenvironment (TME) of LuPSMA therapy patients. <b>Methods:</b> Tumor tissue samples from 61 patients, who were referred for LuPSMA from March 2018 until March 2022, were retrieved. Among these, 40 patients fulfilled all criteria and were therefore included in the analysis. Of these, 3 patients had two biopsies; prior and under systemic treatment, which is why we analyzed 43 samples: 29 (67%) with treatment-naïve tissues samples (cohort 1) and 14 (33%) during systemic treatment. Patients were followed up to assess overall survival. We examined gene expression and immune cell counts (derived from gene expression data) in the two sub-cohorts through transcriptome profiling with the Decipher prostate assay (Veracyte, San Diego, CA), a subset of these patients has been described previously. <b>Results:</b> In the total cohort, the ratio of activated (M1)/naive (M0) macrophages (HR = 0.90 [0.84-0.98]; p = 0.009) was a significant prognosticator of OS. In cohort 1, PD-L2 expression (HR = 1.07 [1.02 - 1.11]; p = 0.003)) and the M1/M0 ratio signature (HR = 0.89 [0.81-0.99]; p = 0.026) were significant independent prognostic factors of OS when analyzed together in a multivariate analysis. AR gene expression was significantly elevated in cohort 2 compared to 1 (p < 0.001). Several DNA repair signatures analyzed were significantly higher in cohort 2 than in cohort 1 (p < 0.05). In cohort 2, PD-L2 expression (HR = 0.87 [0.77 - 0.98]; p = 0.017) emerged as an independent prognostic factor associated with improved OS when included in a multivariate model with the immune 190 score, a negative prognosticator in this analysis (HR = 1.25 [1.02 - 1.53]; p = 0.028). <b>Conclusions:</b> The ratio of M1/M0 macrophages was associated with favorable outcome of LuPSMA in the total cohort of patients. In treatment-naive patient samples, <i>PD-L2</i> expression was associated with unfavorable, whereas M1/M0 macrophages with favorable outcomes, which might indicate that immune checkpoint inhibition could be a combination partner of LuPSMA therapy. In patient biopsy samples acquired after the start of systemic treatment, AR gene expression and DNA repair signatures appear to be significantly altered and <i>PD-L2</i> became a protective marker.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9447-9458"},"PeriodicalIF":13.3,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213590","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}
引用次数: 0
ASIC1a Induces Excessive Mitophagy and PANoptosis of Chondrocyte by the Inhibition of SIRT3 Mitochondrial Translocation. ASIC1a通过抑制SIRT3线粒体易位诱导软骨细胞过度自噬和PANoptosis。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI: 10.7150/thno.116712
Zhuoyan Zai, Xuewen Qian, Yayun Xu, Huifang Lv, Mengjia Hao, Yueming Tao, Lixin Rui, Xiaoyue Zhang, Xiaoqing Peng, Yihao Zhang, Feihu Chen
{"title":"ASIC1a Induces Excessive Mitophagy and PANoptosis of Chondrocyte by the Inhibition of SIRT3 Mitochondrial Translocation.","authors":"Zhuoyan Zai, Xuewen Qian, Yayun Xu, Huifang Lv, Mengjia Hao, Yueming Tao, Lixin Rui, Xiaoyue Zhang, Xiaoqing Peng, Yihao Zhang, Feihu Chen","doi":"10.7150/thno.116712","DOIUrl":"10.7150/thno.116712","url":null,"abstract":"<p><p><b>Rationale:</b> The death of chondrocytes triggered by extracellular acidification represents a critical factor in the degradation of cartilage tissue and bone, thereby exacerbating the progression of rheumatoid arthritis (RA). Our previous research demonstrated that acid-sensing ion channel 1a (ASIC1a) serves as a key acid sensor mediating the destruction of articular cartilage in RA, which is closely associated with mitochondrial damage of chondrocytes. However, its regulatory mechanism remains unclear. <b>Methods:</b> Cartilage samples from RA patients and collagen-induced arthritis (CIA) rat models were examined to determine the levels of mitophagy and PANoptosis. In parallel, primary rat articular chondrocytes were cultured and subjected to either ASIC1a activation or silencing. Mitochondrial function, mitophagy, and PANoptotic markers were evaluated using immunoblotting, immunofluorescence, and transmission electron microscopy. Additionally, the subcellular distribution of SIRT3 to clarify its role in maintaining mitochondrial homeostasis. <b>Results:</b> We observed a significant increase in the levels of mitophagy and PANoptosis within the cartilage tissue of both RA patients and collagen-induced arthritis (CIA) rat models. Activation of ASIC1a by extracellular acidification triggered mitophagy, ultimately resulting in PANoptosis of chondrocytes. The loss of ASIC1a protected chondrocytes from PANoptosis, thereby alleviating disease progression in CIA rats. Mechanistically, we demonstrated that the transport of SIRT3 from cytoplasm to mitochondria was inhibited upon ASIC1a activation. ASIC1a upregulated calcineurin (CaN) expression, which competitively bound to HSP70, disrupting the SIRT3-HSP70 complex and thereby impairing SIRT3 mitochondrial translocation. The reduced levels of SIRT3 in mitochondria induced mitochondrial dysfunction and excessive mitophagy in primary rat articular chondrocytes, ultimately leading to PANoptosis of chondrocytes. Restoration of SIRT3 improved mitochondrial dysfunction and inhibited excessive mitophagy in the process of ASIC1a-induced PANoptosis of chondrocytes. <b>Conclusion:</b> Our study demonstrated that ASIC1a induces the destruction of articular cartilage through the disruption of the equilibrium between mitochondrial quality control and cell fate. This suggests that ASIC1a is a promising therapeutic target to improve the clinical treatment of RA.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9623-9642"},"PeriodicalIF":13.3,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213635","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}
引用次数: 0
Single-cell RNA sequencing reveals endothelial cell heterogeneity and Sox18-mediated EndMT in abdominal aortic aneurysm. 单细胞RNA测序揭示了腹主动脉瘤内皮细胞的异质性和sox18介导的EndMT。
IF 13.3 1区 医学
Theranostics Pub Date : 2025-08-30 eCollection Date: 2025-01-01 DOI: 10.7150/thno.110254
Xianxian Wu, Xuanyu Liu, Yuanzhi Cheng, Yuhan Zhang, Dou Shi, Yang Shi, Xing Liu, Jianghao Feng, Anxiong Long, Wei Hu, Zhiwei Yang
{"title":"Single-cell RNA sequencing reveals endothelial cell heterogeneity and Sox18-mediated EndMT in abdominal aortic aneurysm.","authors":"Xianxian Wu, Xuanyu Liu, Yuanzhi Cheng, Yuhan Zhang, Dou Shi, Yang Shi, Xing Liu, Jianghao Feng, Anxiong Long, Wei Hu, Zhiwei Yang","doi":"10.7150/thno.110254","DOIUrl":"10.7150/thno.110254","url":null,"abstract":"<p><p><b>Rationale:</b> Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease lacking clinical predictors and effective pharmacologic therapies. The cellular heterogeneity and molecular changes of different cell types during AAA have been revealed in human and mouse aortas by single-cell RNA sequencing (scRNA-seq) technology. However, the heterogeneity and plasticity of endothelial cells (ECs) in AAA remain poorly characterized. <b>Methods:</b> scRNA-seq was performed on the abdominal aorta from angiotensin II (AngⅡ) and salt-induced AAA mice. Additionally, public scRNA-seq data of human and mouse AAA were analyzed with a focus on ECs. Cellular and animal experiments were conducted to validate EC heterogeneity and to investigate the role of SRY (sex-determining region on the Y chromosome)-box transcription factor 18 (Sox18) in endothelial-to-mesenchymal transition (EndMT) during AAA formation. <b>Results:</b> Unbiased clustering analysis identified 20 clusters encompassing 11 cell types. Four subpopulations of ECs were identified in AngⅡ and salt-induced mouse AAA models: <i>Cd36</i> <sup>+</sup> lipid-handling ECs, <i>Fn1</i> <sup>+</sup> mesenchymal-like ECs, <i>Lrg1<sup>+</sup></i> pleiotropically activated ECs, and <i>Mmrn1</i> <sup>+</sup> lymphatic-like ECs. Similar results were observed in human AAA scRNA-seq data. Endothelial dysfunction and EndMT were detected at single cell solution and validated experimentally. Sox18 was identified as a potential EndMT regulator. Sox18 downregulation was confirmed in both human and mouse aortic aneurysm. <i>In vitro</i>, Sox18 siRNA transfection induced EndMT and increased EC permeability via PI3K/Akt signaling pathway. <i>In vivo</i>, EC-specific Sox18 overexpression inhibited EndMT and attenuated AAA formation. <b>Conclusion:</b> Our data reveal the heterogeneity and transcriptional signatures of ECs in AAA at single cell solution, and demonstrate the previously unrecognized role of Sox18-mediated EndMT in AAA, providing novel insights and a promising therapeutic target for AAA intervention.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 18","pages":"9486-9507"},"PeriodicalIF":13.3,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213670","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}
引用次数: 0
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