Theranostics最新文献

{"title":"S100A proteins show a spatial distribution of inflammation associated with the glioblastoma microenvironment architecture.","authors":"Blanca Cómitre-Mariano, Berta Segura-Collar, Gabriel Vellila-Alonso, Rubén Contreras, Aurelio Henandez-Lain, Manuel Valiente, Juan M Sepulveda, Stephen Garrett Marcus, Guillermo García-Posadas, Luis Jiménez-Roldán, Ángel Perez-Nuñez, Ricardo Gargini","doi":"10.7150/thno.100638","DOIUrl":"10.7150/thno.100638","url":null,"abstract":"<p><p><b>Background:</b> Glioblastoma IDH wild type (GBM IDH wt) has a poor prognosis and a strongly associated with inflammatory processes. Inflammatory molecules generate positive feedback with tumor cells fueling tumor growth as well as recruitment of immune cells that promote aggressiveness. Although the role of many inflammatory molecules is well known, there are many macromolecules, such as the S100A proteins, whose role is only now beginning to be established. <b>Methods:</b> Using RNA-seq, bioinformatics tools and a cohort of glioma patients to validate the results, we have analysed the inflammatory processes involved in glioma. Transcriptional profiles were also used to define biological processes of relevance to specific S100A proteins. Finally, we characterized the relevant immune populations with an IHC analysis and transcriptional profiling. <b>Results:</b> We have noted an increased expression of S100A in GBM IDH wt compared to gliomas IDH mutants. This allowed us to analyse the involvement of different members of the family, such as S100A9, A11 and A13 as possible regulators of inflammatory processes in the GBM-IDH wt microenvironment. Thus, we observed that S100A9 is located in hypoxic areas linked to the function of neutrophils, S100A11 is found in vascular areas associated with the function of perivascular pericytes and macrophages, and finally, S100A13 which is related to the dysfunction of microglia. <b>Conclusion:</b> Our findings define different functions for S100A9, A11 and A13 proteins that are associated with the architecture of the glioblastoma microenvironment and define its progression. Moreover, these alterations can be reversed by the RAGE inhibitor, Azeliragon which is in a phase I/II clinical trial NCT05635734.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"726-744"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A H2S-activated NIR-II imaging probe for precise diagnosis and pathological evaluation of colorectal tumor.","authors":"Yu Ji, Qinxian Huang, Qian Jia, Haohao Yan, Yajing Chi, Yuanyuan Jia, Chaoqiang Qiao, Yanbin Feng, Zuo Yang, Ruili Zhang, Zhongliang Wang","doi":"10.7150/thno.103999","DOIUrl":"10.7150/thno.103999","url":null,"abstract":"<p><p><b>Rationale:</b> The quick and accurate detection of colorectal cancer (CRC) is essential for improving the treatment efficacy and patient survival, which nevertheless remains challenging due to low specificity and sensitivity of current CRC diagnostic approaches. Therefore, providing a robust solution for real-time and accurate tumor delineation is highly desirable. <b>Methods:</b> We report a novel polyacrylic acid-mediated strategy to develop the endogenous hydrogen sulfide (H₂S)-activated NIR-II probe DCNP@PB for specific visualization of CRC and image-guided tumor surgery. The stability, biocompatibility, H₂S-responsiveness, and NIR-II imaging capability were evaluated <i>in vitro</i> and <i>in vivo</i>. Human CRC tissues were used to evaluated the performance of the DCNP@PB. <b>Results:</b> By exploiting the effective inner filter effect (IFE) and fluorescence resonance energy transfer (FRET) between DCNPs and PB, luminescence of DCNP@PB can be rapidly switched ON in response to H₂S in colorectal tumor, affording high tumor-to-background ratio (TBR). Notably, H₂S-responsive range of DCNP@PB well matches the H₂S concentration at tumor site, thereby minimizing nonspecific activation by other sulfur-containing substances in a complicated biological environment. Such accurate H₂S responsiveness not only benefits the differentiation between tumor and normal tissues in the mouse model, but also clearly delineates the cancerous boundaries in human tissues specimens. <b>Conclusion:</b> This work presents not only a promising example of H₂S-activated NIR-II optical probe that could be intravenously injected for <i>in vivo</i> applications to afford reliable information and quick feedback, but also an effective strategy to design the activatable imaging probes for precise tumor diagnosis and intraoperative decision support.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"189-201"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915715","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":"Ultra-small quercetin-based nanotherapeutics ameliorate acute liver failure by combatting inflammation/cellular senescence cycle.","authors":"Yali Feng, Xiaoli Zhang, Juan Li, Shan Fu, Weicheng Xu, Jinfeng Liu, Yuan Yang, Tianyan Chen, Yingren Zhao, Dongmin Li, Mingzhen Zhang, Yingli He","doi":"10.7150/thno.103746","DOIUrl":"https://doi.org/10.7150/thno.103746","url":null,"abstract":"<p><p><b>Background:</b> Acute liver failure (ALF) is marked by a substantial generation of reactive oxygen species (ROS), which can induce both cellular senescence and a pronounced inflammatory response. Senescent cells secrete factors collectively termed the senescence-associated secretory phenotype (SASP), which exacerbate inflammation, while inflammation can reciprocally promote cellular senescence. Quercetin (Que), recognized for its ROS-scavenging capabilities, holds the potential for anti-inflammatory and anti-senescent effects. However, its extremely low aqueous solubility constrains its clinical efficacy in treating inflammation. <b>Methods:</b> We employed a simple and stable coordination method to synthesize ultra-small quercetin-Fe nanoparticles (QFN) by complexing quercetin with iron ions. The ROS-scavenging, anti-inflammatory, and anti-senescent effects of QFN were evaluated <i>in vitro</i>. A lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice model was used to investigate the therapeutic effects of QFN <i>in vivo</i>, and transcriptomic analysis was conducted to elucidate the mechanisms underlying QFN-mediated hepatoprotection. <b>Results:</b> Our findings demonstrate that QFN possesses remarkable water solubility and highly efficient ROS-scavenging properties. <i>In vitro</i>, QFN effectively inhibits macrophage-mediated inflammation and mitigates hepatocyte senescence. <i>In vivo</i>, QFN significantly attenuates LPS/D-GalN-induced ALF by protecting against macrophage inflammation and cellular senescence, thereby disrupting the self-perpetuating cycle of inflammation and aging. Moreover, its potent ROS scavenging capacity not only suppresses cellular apoptosis but also facilitates liver regeneration. Transcriptomic analyses further reveal that QFN exerts its protective effects through the modulation of key pathways involved in cellular senescence and inflammation. <b>Conclusions:</b> In summary, our study characterizes QFN as a potent ROS-scavenging modulator that exhibits both anti-inflammatory and anti-senescent properties, effectively disrupting the detrimental feedback loop between inflammation and cellular senescence. QFN holds considerable potential as a therapeutic agent for the treatment of ALF and other pathologies associated with inflammation and aging.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 3","pages":"1035-1056"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955416","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":"First clinical utility of sensing Ultrasound Localization Microscopy (sULM): identifying renal pseudotumors.","authors":"Sylvain Bodard, Louise Denis, Georges Chabouh, Dany Anglicheau, Olivier Hélénon, Jean-Michel Correas, Olivier Couture","doi":"10.7150/thno.100897","DOIUrl":"10.7150/thno.100897","url":null,"abstract":"<p><p><b>Rationale:</b> Renal pseudotumors, which mimic tumors on imaging, pose diagnostic challenges that can lead to unnecessary interventions. Sensing ultrasound localization microscopy (sULM) is an advanced imaging technique that uses ultrasound imaging and microbubbles as sensors to visualize kidney functional units. This study aims to investigate whether sULM could differentiate between renal pseudotumors and tumors based on the presence of glomeruli. <b>Methods:</b> Eleven patients (6 tumors, 6 pseudotumors - 1 patient with 2 pseudotumors) were included. Data on patient demographics, tumor characteristics, and sULM metrics were collected. Glomeruli were quantified and compared among tumors, pseudotumors, and renal cortex using sULM. Additional metrics, i.e., normalized speed and dispersity, were also analyzed. <b>Results:</b> Renal tumors exhibited fewer detected glomeruli paths (mean: 10 ± 6 /cm² [range: 4-20]) compared to pseudotumors (26 ± 5 /cm² [19-32], p < 0.001) and normal renal cortex (26 ± 6 /cm² [15-35], p < 0.01). Tumors displayed lower dispersity (0.13 ± 0.06 arbitrary units [a.u.] [0.07-0.20]) than both the renal cortex (0.3 ± 0.1 a.u. [0.1-0.4], p = 0.0012) and pseudotumors (0.22 ± 0.05 a.u. [0.16-0.25], p = 0.0389), and lower normalized speeds of 0.08 ± 0.04 without units (w.u.) [range: 0.03-0.17] compared to the renal cortex (0.18 ± 0.07 w.u. [0.11-0.28], p = 0.0014) and pseudotumors (0.14 ± 0.02 w.u. [0.12-0.16], p = 0.0497). sULM could effectively differentiate renal pseudotumors from tumors based on glomerular detection and metrics estimation. <b>Conclusion:</b> This initial exploration into the clinical utility of sULM suggests it could provide a noninvasive tool to support patient management, particularly for individuals with contraindications to conventional imaging methods. Further studies are needed to confirm these preliminary findings.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"233-244"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915022","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":"Bisphosphonate-mineralized nano-IFNγ suppresses residual tumor growth caused by incomplete radiofrequency ablation through metabolically remodeling tumor-associated macrophages.","authors":"Zhicheng Yan, Bing Wang, Yuhan Shen, Junji Ren, Meifang Chen, Yunhui Jiang, Hao Wu, Wenbing Dai, Hua Zhang, Xueqing Wang, Qiang Zhang, Wei Yang, Bing He","doi":"10.7150/thno.100998","DOIUrl":"https://doi.org/10.7150/thno.100998","url":null,"abstract":"<p><p><b>Rationale:</b> Radiofrequency ablation (RFA), as a minimally invasive surgery strategy based on local thermal-killing effect, is widely used in the clinical treatment of multiple solid tumors. Nevertheless, RFA cannot achieve the complete elimination of tumor lesions with larger burden or proximity to blood vessels. Incomplete RFA (iRFA) has even been validated to promote residual tumor growth due to the suppressive tumor immune microenvironment (TIME). Therefore, exploring strategies to remodel TIME is a key issue for the development of RFA therapy. <b>Methods:</b> The negative effect of iRFA on colorectal cancer therapy was firstly investigated. Then a zoledronate-mineralized nanoparticle loaded with IFNγ (Nano-IFNγ/Zole) was designed and its tumor suppressive efficacy was evaluated. Finally, the metabolic reprogramming mechanism of Nano-IFNγ/Zole on tumor-associated macrophages (TAMs) was studied in detail. <b>Results:</b> We found iRFA dynamically altered TIME and promoted TAM differentiation from M1 to M2. Nano-IFNγ/Zole was fabricated to metabolically remodel TAMs. IFNγ in Nano-IFNγ/Zole concentrated in the ablation site to play a long-term remodeling role. Acting on mevalonate pathway, Nano-IFNγ/Zole was discovered to reduce lysosomal acidification and activate transcription factor TFEB by inhibiting isoprene modification of the Rab protein family. These mechanisms, in conjunction with IFNγ-activated JAK/STAT1 signaling, accelerated the reprogramming of TAMs from M2 to M1, and suppressed tumor recurrence after iRFA. <b>Conclusions:</b> This study elaborates the synergistic mechanism of zoledronate and IFNγ in Nano-IFNγ/Zole to reshape suppressive TIME caused by iRFA by remodeling TAMs, and highlights the important value of metabolically induced cellular reprogramming. Since both zoledronate and IFNγ have already been approved in clinics, this integrative nano-drug delivery system establishes an effective strategy with great translational promise to overcome the poor prognosis after clinically incomplete RFA.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 3","pages":"1057-1076"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955521","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":"Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.","authors":"Mingxia Jiang, Huapan Fang, Huayu Tian","doi":"10.7150/thno.103376","DOIUrl":"10.7150/thno.103376","url":null,"abstract":"<p><p>The metabolism of cancer and immune cells plays a crucial role in the initiation, progression, and metastasis of cancer. Cancer cells often undergo metabolic reprogramming to sustain their rapid growth and proliferation, along with meeting their energy demands and biosynthetic needs. Nevertheless, immune cells execute their immune response functions through the specific metabolic pathways, either to recognize, attack, and eliminate cancer cells or to promote the growth or metastasis of cancer cells. The alteration of cancer niches will impact the metabolism of both cancer and immune cells, modulating the survival and proliferation of cancer cells, and the activation and efficacy of immune cells. This review systematically describes the key characteristics of cancer cell metabolism and elucidates how such metabolic traits influence the metabolic behavior of immune cells. Moreover, this article also highlights the crucial role of immune cell metabolism in anti-tumor immune responses, particularly in priming T cell activation and function. By comprehensively exploring the metabolic crosstalk between cancer and immune cells in cancer niche, the aim is to discover novel strategies of cancer immunotherapy and provide effective guidance for clinical research in cancer treatment. In addition, the review also discusses current challenges such as the inadequacy of relevant diagnostic technologies and the issue of multidrug resistance, and proposes potential solutions including bolstering foundational cancer research, fostering technological innovation, and implementing precision medicine approaches. In-depth research into the metabolic effects of cancer niches can improve cancer treatment outcomes, prolong patients' survival period and enhance their quality of life.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"155-188"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915528","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":"Optical coherence tomography (OCT) and OCT angiography: Technological development and applications in brain science.","authors":"Luyao Yang, Pengyu Chen, Xiaofei Wen, Qingliang Zhao","doi":"10.7150/thno.97192","DOIUrl":"10.7150/thno.97192","url":null,"abstract":"<p><p>Brain diseases are a leading cause of disability and death worldwide. Early detection can lead to earlier intervention and better outcomes for patients. In recent years, optical coherence tomography (OCT) and OCT angiography (OCTA) imaging have been widely used in stroke, traumatic brain injury (TBI), and brain cancer due to their advantages of <i>in vivo</i>, unlabeled, and high-resolution 3D microvessel imaging at the capillary resolution level. This review summarizes recent advances and challenges in living brain imaging using OCT/OCTA, including technique modality, types of diseases, and theoretical approach. Although there may still be many limitations, with the development of lasers and the advances in artificial intelligence are expected to enable accurate detection of deep cerebral hemodynamics and guide intraoperative tumor resection <i>in vivo</i> in the future.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 1","pages":"122-140"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915530","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":"Advances in adhesive hydrogels applied for ophthalmology: An overview focused on the treatment.","authors":"Ke Yan, Qinghe Zhang, Qiuping Liu, Yi Han, Zuguo Liu","doi":"10.7150/thno.103266","DOIUrl":"10.7150/thno.103266","url":null,"abstract":"<p><p>Adhesive hydrogels, composed of hydrophilic polymers arranged in a three-dimensional network, have emerged as a pivotal innovation in ophthalmology due to their ability to securely adhere to ocular tissues while providing sustained therapeutic effects. The eye, with its delicate structure and specific needs, presents unique challenges for drug delivery and tissue regeneration. This review explores the transformative potential of adhesive hydrogels in addressing these challenges across a range of ocular conditions, including corneal injuries, cataracts, glaucoma, vitreoretinal disorders, and ocular trauma. By detailing the mechanisms of polymerization and adhesion, this paper highlights how these materials can be customized for specific ophthalmic applications, offering insights into their current use and future possibilities. The emphasis is placed on the clinical significance and future directions of adhesive hydrogels in advancing ophthalmic therapy, potentially revolutionizing the treatment of complex eye diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 3","pages":"915-942"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955498","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":"Metformin-based nanomedicines for reprogramming tumor immune microenvironment.","authors":"Jieyu Liu, Xiaoling Li, Yinggang Li, Qiyong Gong, Kui Luo","doi":"10.7150/thno.104872","DOIUrl":"10.7150/thno.104872","url":null,"abstract":"<p><p>Immunotherapy has transformed current cancer management, and it has achieved significant progress over last decades. However, an immunosuppressive tumor microenvironment (TME) diminishes the effectiveness of immunotherapy by suppressing the activity of immune cells and facilitating tumor immune-evasion. Adenosine monophosphate-activated protein kinase (AMPK), a key modulator of cellular energy metabolism and homeostasis, has gained growing attention in anti-tumor immunity. Metformin is usually considered as a cornerstone in diabetes management, and its role in activating the AMPK pathway has also been extensively explored in cancer therapy although the findings on its role remain inconsistent. Metformin in a nanomedicine formulation has been found to hold potential in reprogramming the immunosuppressive TME through immunometabolic modulation of both tumor and immune cells. This review elaborates the foundation and progress of immunometabolic reprogramming of the TME via metformin-based nanomedicines, offering valuable insights for the next generation of cancer therapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 3","pages":"993-1016"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955517","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 nitric oxide synthase transforms carotid occlusion-mediated benign oligemia into <i>de novo</i> large cerebral infarction.","authors":"Ha Kim, Jinyong Chung, Jeong Wook Kang, Dawid Schellingerhout, Soo Ji Lee, Hee Jeong Jang, Inyeong Park, Taesu Kim, Dong-Seok Gwak, Ji Sung Lee, Sung-Ha Hong, Kang-Hoon Je, Hee-Joon Bae, Joohon Sung, Eng H Lo, James Faber, Cenk Ayata, Dong-Eog Kim","doi":"10.7150/thno.104132","DOIUrl":"10.7150/thno.104132","url":null,"abstract":"<p><p><b>Rationale:</b> It remains unclear why unilateral proximal carotid artery occlusion (UCAO) causes benign oligemia in mice, yet leads to various outcomes (asymptomatic-to-death) in humans. We hypothesized that inhibition of nitric oxide synthase (NOS) both transforms UCAO-mediated oligemia into full infarction and expands pre-existing infarction. <b>Methods:</b> Using 900 mice, we i) investigated stroke-related effects of UCAO with/without intraperitoneal administration of the NOS inhibitor (NOSi) N_ω-nitro-L-arginine methyl ester (L-NAME, 400 mg/kg); ii) examined the rescue effect of the NO-donor, molsidomine (200 mg/kg at 30 minutes); and iii) tested the impact of antiplatelet medications. To corroborate preclinical findings, we conducted clinical studies. <b>Results:</b> UCAO alone induced infarction rarely (~2%) or occasionally (~14%) in C57BL/6 and BALB/c mice, respectively. However, L-NAME+UCAO induced large-arterial infarction in ~75% of C57BL/6 and BALB/c mice. Six-hour laser-speckle imaging detected spreading ischemia in ~40% of C57BL/6 and BALB/c mice with infarction (vs. none without) by 24-hours. In agreement with vasoconstriction/microthrombus formation shown by intravital-microscopy, molsidomine and the endothelial-NOS-activating antiplatelet cilostazol attenuated/prevented progression to infarction. Moreover, UCAO without L-NAME caused infarction in ~22% C57BL/6 and ~31% ApoE knock-out mice with hyperglycemia/hyperlipidemia, which associated with ~60% greater levels of symmetric dimethylarginine (SDMA, an endogenous NOSi). Further, increased levels of glucose and cholesterol associated with significantly larger infarct volumes in 438 UCAO-stroke patients. Lastly, Mendelian randomization identified a causative role of NOS inhibition (elevated SDMA concentration) in ischemic stroke risk (OR = 1.24; 95% CI, 1.11-1.38; <i>P</i> = 7.69×10^-5). <b>Conclusion:</b> NOS activity determines the fate of hypoperfused brain following acute UCAO, where SDMA could be a potential risk predictor.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 2","pages":"585-604"},"PeriodicalIF":12.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915532","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}