Theranostics最新文献

{"title":"Biomimetic nanoparticles with enhanced rapamycin delivery for autism spectrum disorder treatment via autophagy activation and oxidative stress modulation.","authors":"Chenlin Miao, Yizhe Shen, Yue Lang, Hui Li, Yan Gong, Yamei Liu, Huafei Li, Byron C Jones, Fuxue Chen, Shini Feng","doi":"10.7150/thno.95614","DOIUrl":"10.7150/thno.95614","url":null,"abstract":"<p><p><b>Rationale:</b> Autism spectrum disorder (ASD) represents a complex neurodevelopmental condition lacking specific pharmacological interventions. Given the multifaced etiology of ASD, there exist no effective treatment for ASD. Rapamycin (RAPA) can activate autophagy by inhibiting the mTOR pathway and has exhibited promising effects in treating central nervous system disorders; however, its limited ability to cross the blood-brain barrier (BBB) has hindered its clinical efficacy, leading to substantial side effects. <b>Methods:</b> To address this challenge, we designed a drug delivery system utilizing red blood cell membrane (CM) vesicles modified with SS31 peptides to enhance the brain penetration of RAPA for the treatment of autism. <b>Results:</b> The fabricated SCM@RAPA nanoparticles, with an average diameter of 110 nm, exhibit rapid release of RAPA in a pathological environment characterized by oxidative stress. <i>In vitro</i> results demonstrate that SCM@RAPA effectively activate cellular autophagy, reduce intracellular ROS levels, improve mitochondrial function, thereby ameliorating neuronal damage. SS31 peptide modification significantly enhances the BBB penetration and rapid brain accumulation of SCM@RAPA. Notably, SCM@RAPA nanoparticles demonstrate the potential to ameliorate social deficits, improve cognitive function, and reverse neuronal impairments in valproic acid (VPA)-induced ASD models. <b>Conclusions:</b> The therapeutic potential of SCM@RAPA in managing ASD signifies a paradigm shift in autism drug treatment, holding promise for clinical interventions in diverse neurological conditions.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902934","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":"Unlocking potential of oxytocin: improving intracranial lymphatic drainage for Alzheimer's disease treatment.","authors":"Caihua Ye, Shengnan Wang, Lin Niu, Fan Yang, Guohe Wang, Siqi Wang, Jiamei Xie, Yihan Chen, Jinbo Qi, Hui Shen, Yan Dou, Junping Wang","doi":"10.7150/thno.98587","DOIUrl":"10.7150/thno.98587","url":null,"abstract":"<p><p><b>Background:</b> The impediment to β-amyloid (Aβ) clearance caused by the invalid intracranial lymphatic drainage in Alzheimer's disease is pivotal to its pathogenesis, and finding reliable clinical available solutions to address this challenge remains elusive. <b>Methods:</b> The potential role and underlying mechanisms of intranasal oxytocin administration, an approved clinical intervention, in improving intracranial lymphatic drainage in middle-old-aged APP/PS1 mice were investigated by live mouse imaging, ASL/CEST-MRI scanning, in vivo two-photon imaging, immunofluorescence staining, ELISA, RT-qPCR, Western blotting, RNA-seq analysis, and cognitive behavioral tests. <b>Results:</b> Benefiting from multifaceted modulation of cerebral hemodynamics, aquaporin-4 polarization, meningeal lymphangiogenesis and transcriptional profiles, oxytocin administration normalized the structure and function of both the glymphatic and meningeal lymphatic systems severely impaired in middle-old-aged APP/PS1 mice. Consequently, this intervention facilitated the efficient drainage of Aβ from the brain parenchyma to the cerebrospinal fluid and then to the deep cervical lymph nodes for efficient clearance, as well as improvements in cognitive deficits. <b>Conclusion:</b> This work broadens the underlying neuroprotective mechanisms and clinical applications of oxytocin medication, showcasing its promising therapeutic prospects in central nervous system diseases with intracranial lymphatic dysfunction.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902986","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":"Microfluidic chips in female reproduction: a systematic review of status, advances, and challenges.","authors":"Tong Wu, Jinfeng Yan, Kebing Nie, Ying Chen, Yangyang Wu, Shixuan Wang, Jinjin Zhang","doi":"10.7150/thno.97301","DOIUrl":"10.7150/thno.97301","url":null,"abstract":"<p><p>The female reproductive system is essential to women's health, human reproduction and societal well-being. However, the clinical translation of traditional research models is restricted due to the uncertain effects and low efficiency. Emerging evidence shows that microfluidic chips provide valuable platforms for studying the female reproductive system, while no paper has ever comprehensively discussed the topic. Here, a total of 161 studies out of 14,669 records are identified in PubMed, Scopus, Web of Science, ScienceDirect and IEEE Xplore databases. Among these, 61 studies focus on oocytes, which further involves culture, cell surgeries (oocyte separation, rotation, enucleation, and denudation), evaluation and cryopreservation. Forty studies investigate embryo manipulation via microfluidic chips, covering <i>in vitro</i> fertilization, cryopreservation and functional evaluation. Forty-six studies reconstitute both the physiological and pathological statuses of <i>in vivo</i> organs, mostly involved in placenta and fetal membrane research. Fourteen studies perform drug screening and toxicity testing. In this review, we summarize the current application of microfluidic chips in studying the female reproductive system, the advancements in materials and methods, and discuss the future challenges. The present evidence suggests that microfluidic chips-assisted reproductive system reconstruction is promising and more studies are urgently needed.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303079/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902941","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":"Palladium-103 (¹⁰³Pd/^103mRh), a promising Auger-electron emitter for targeted radionuclide therapy of disseminated tumor cells - absorbed doses in single cells and clusters, with comparison to ¹⁷⁷Lu and ¹⁶¹Tb.","authors":"Elif Hindié, Alexandre Larouze, Mario Alcocer-Ávila, Clément Morgat, Christophe Champion","doi":"10.7150/thno.95436","DOIUrl":"10.7150/thno.95436","url":null,"abstract":"<p><p>Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure. Selection of appropriate radionuclides is required. This work highlights the potential of ¹⁰³Pd (T_1/2 = 16.991 d) which decays to ^103mRh (T_1/2 = 56.12 min) then to stable ¹⁰³Rh with emission of Auger and conversion electrons. <b>Methods:</b> The Monte Carlo track structure code CELLDOSE was used to assess absorbed doses in single cells (14-μm diameter; 10-μm nucleus) and clusters of 19 cells. The radionuclide was distributed on the cell surface, within the cytoplasm, or in the nucleus. Absorbed doses from ¹⁰³Pd, ¹⁷⁷Lu and ¹⁶¹Tb were compared after energy normalization. The impact of non-uniform cell targeting, and the potential benefit from dual-targeting was investigated. Additional results related to ^103mRh, if used directly, are provided. <b>Results:</b> In the single cell, and depending on radionuclide distribution, ¹⁰³Pd delivered 7- to 10-fold higher nuclear absorbed dose and 9- to 25-fold higher membrane dose than ¹⁷⁷Lu. In the 19-cell clusters, ¹⁰³Pd absorbed doses also largely exceeded ¹⁷⁷Lu. In both situations, ¹⁶¹Tb stood in-between ¹⁰³Pd and ¹⁷⁷Lu. Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity. For example, with intranuclear ¹⁰³Pd, unlabeled cells received only 14% of the expected nuclear dose. Targeting with two ¹⁰³Pd-labeled radiopharmaceuticals minimized dose heterogeneity. <b>Conclusion:</b> ¹⁰³Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than ¹⁷⁷Lu to single tumor cells and cell clusters. This may open new horizons for the use of TRT in adjuvant or neoadjuvant settings, or for targeting minimal residual disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902980","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":"Multifunctional hydrogel-based engineered extracellular vesicles delivery for complicated wound healing.","authors":"Zuhao Li, Jinlong Liu, Jian Song, Zhifeng Yin, Fengjin Zhou, Hao Shen, Guangchao Wang, Jiacan Su","doi":"10.7150/thno.97317","DOIUrl":"10.7150/thno.97317","url":null,"abstract":"<p><p>The utilization of extracellular vesicles (EVs) in wound healing has been well-documented. However, the direct administration of free EVs via subcutaneous injection at wound sites may result in the rapid dissipation of bioactive components and diminished therapeutic efficacy. Functionalized hydrogels provide effective protection, as well as ensure the sustained release and bioactivity of EVs during the wound healing process, making them an ideal candidate material for delivering EVs. In this review, we introduce the mechanisms by which EVs accelerate wound healing, and then elaborate on the construction strategies for engineered EVs. Subsequently, we discuss the synthesis strategies and application of hydrogels as delivery systems for the sustained release of EVs to enhance complicated wound healing. Furthermore, in the face of complicated wounds, functionalized hydrogels with specific wound microenvironment regulation capabilities, such as antimicrobial, anti-inflammatory, and immune regulation, used for loading engineered EVs, provide potential approaches to addressing these healing challenges. Ultimately, we deliberate on potential future trajectories and outlooks, offering a fresh viewpoint on the advancement of artificial intelligence (AI)-energized materials and 3D bio-printed multifunctional hydrogel-based engineered EVs delivery dressings for biomedical applications.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902942","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":"Pioneering noninvasive colorectal cancer detection with an AI-enhanced breath volatilomics platform.","authors":"Yongqian Liu, Yongyan Ji, Jian Chen, Yixuan Zhang, Xiaowen Li, Xiang Li","doi":"10.7150/thno.94950","DOIUrl":"10.7150/thno.94950","url":null,"abstract":"<p><p><b>Background:</b> The sensitivity and specificity of current breath biomarkers are often inadequate for effective cancer screening, particularly in colorectal cancer (CRC). While a few exhaled biomarkers in CRC exhibit high specificity, they lack the requisite sensitivity for early-stage detection, thereby limiting improvements in patient survival rates. <b>Methods:</b> In this study, we developed an advanced Mass Spectrometry-based volatilomics platform, complemented by an enhanced breath sampler. The platform integrates artificial intelligence (AI)-assisted algorithms to detect multiple volatile organic compounds (VOCs) biomarkers in human breath. Subsequently, we applied this platform to analyze 364 clinical CRC and normal exhaled samples. <b>Results:</b> The diagnostic signatures, including 2-methyl, octane, and butyric acid, generated by the platform effectively discriminated CRC patients from normal controls with high sensitivity (89.7%), specificity (86.8%), and accuracy (AUC = 0.91). Furthermore, the metastatic signature correctly identified over 50% of metastatic patients who tested negative for carcinoembryonic antigen (CEA). Fecal validation indicated that elevated breath biomarkers correlated with an inflammatory response guided by Bacteroides fragilis in CRC. <b>Conclusion:</b> This study introduces a sophisticated AI-aided Mass Spectrometry-based platform capable of identifying novel and feasible breath biomarkers for early-stage CRC detection. The promising results position the platform as an efficient noninvasive screening test for clinical applications, offering potential advancements in early detection and improved survival rates for CRC patients.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902981","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":"Astrocyte-derived lactate aggravates brain injury of ischemic stroke in mice by promoting the formation of protein lactylation.","authors":"Xiao-Yi Xiong, Xin-Ru Pan, Xia-Xia Luo, Yu-Fei Wang, Xin-Xiao Zhang, Su-Hao Yang, Zhan-Qiong Zhong, Chang Liu, Qiong Chen, Peng-Fei Wang, Xiao-Wei Chen, Shu-Guang Yu, Qing-Wu Yang","doi":"10.7150/thno.96375","DOIUrl":"10.7150/thno.96375","url":null,"abstract":"<p><p><b>Aim:</b> Although lactate supplementation at the reperfusion stage of ischemic stroke has been shown to offer neuroprotection, whether the role of accumulated lactate at the ischemia phase is neuroprotection or not remains largely unknown. Thus, in this study, we aimed to investigate the roles and mechanisms of accumulated brain lactate at the ischemia stage in regulating brain injury of ischemic stroke. <b>Methods and Results:</b> Pharmacological inhibition of lactate production by either inhibiting LDHA or glycolysis markedly attenuated the mouse brain injury of ischemic stroke. In contrast, additional lactate supplement further aggravates brain injury, which may be closely related to the induction of neuronal death and A1 astrocytes. The contributing roles of increased lactate at the ischemic stage may be related to the promotive formation of protein lysine lactylation (Kla), while the post-treatment of lactate at the reperfusion stage did not influence the brain protein Kla levels with neuroprotection. Increased protein Kla levels were found mainly in neurons by the HPLC-MS/MS analysis and immunofluorescent staining. Then, pharmacological inhibition of lactate production or blocking the lactate shuttle to neurons showed markedly decreased protein Kla levels in the ischemic brains. Additionally, <i>Ldha</i> specific knockout in astrocytes (<i>Aldh1l1</i> ^CreERT2; <i>Ldha</i> ^fl/fl mice, cKO) mice with MCAO were constructed and the results showed that the protein Kla level was decreased accompanied by a decrease in the volume of cerebral infarction in cKO mice compared to the control groups. Furthermore, blocking the protein Kla formation by inhibiting the writer p300 with its antagonist A-485 significantly alleviates neuronal death and glial activation of cerebral ischemia with a reduction in the protein Kla level, resulting in extending reperfusion window and improving functional recovery for ischemic stroke. <b>Conclusion:</b> Collectively, increased brain lactate derived from astrocytes aggravates ischemic brain injury by promoting the protein Kla formation, suggesting that inhibiting lactate production or the formation of protein Kla at the ischemia stage presents new therapeutic targets for the treatment of ischemic stroke.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902933","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":"⁶⁸Ga-labeled fibroblast activation protein inhibitor (FAPI) PET/CT for locally advanced or recurrent pancreatic cancer staging and restaging after chemoradiotherapy.","authors":"Giulia Metzger, Christian Bayerl, Julian Mm Rogasch, Christian Furth, Christoph Wetz, Marcus Beck, Felix Mehrhof, Holger Amthauer, Pirus Ghadjar, Christopher Neumann, Uwe Pelzer, Daniel Zips, Frank Hofheinz, Jane Grabowski, Imke Schatka, Sebastian Zschaeck","doi":"10.7150/thno.95329","DOIUrl":"10.7150/thno.95329","url":null,"abstract":"<p><p><b>Purpose:</b> ⁶⁸Ga-labeled fibroblast activation protein inhibitor (FAPI) is a novel PET tracer with great potential for staging pancreatic cancer. Data on locally advanced or recurrent disease is sparse, especially on tracer uptake before and after high dose chemoradiotherapy (CRT). The aim of this study was to evaluate [⁶⁸Ga]Ga-FAPI-46 PET/CT staging in this setting. <b>Methods:</b> Twenty-seven patients with locally recurrent or locally advanced pancreatic adenocarcinoma (LRPAC n = 15, LAPAC n = 12) in stable disease or partial remission after chemotherapy underwent FAPI PET/CT and received consolidation CRT in stage M0 with follow-up FAPI PET/CT every three months until systemic progression. Quantitative PET parameters SUV_max, SUV_mean, FAPI-derived tumor volume and total lesion FAPI-uptake were measured in baseline and follow-up PET/CT scans. Contrast-enhanced CT (ceCT) and PET/CT data were evaluated blinded and staged according to TNM classification. <b>Results:</b> FAPI PET/CT modified staging compared to ceCT alone in 23 of 27 patients in baseline, resulting in major treatment alterations in 52% of all patients (30%: target volume adjustment due to N downstaging, 15%: switch to palliative systemic chemotherapy only due to diffuse metastases, 7%: abortion of radiotherapy due to other reasons). Regarding follow-up scans, major treatment alterations after performing FAPI PET/CT were noted in eleven of 24 follow-up scans (46%) with switch to systemic chemotherapy or best supportive care due to M upstaging and ablative radiotherapy of distant lymph node and oligometastasis. Unexpectedly, in more than 90 % of the follow-up scans, radiotherapy did not induce local fibrosis related FAPI uptake. During the first follow-up, all quantitative PET metrics decreased, and irradiated lesions showed significantly lower FAPI uptake in locally controlled disease (SUV_max p = 0.047, SUV_mean p = 0.0092) compared to local failure. <b>Conclusion:</b> Compared to ceCT, FAPI PET/CT led to major therapeutic alterations in patients with LRPAC and LAPAC prior to and after radiotherapy, which might help identify patients benefiting from adjustments in every treatment stage. FAPI PET/CT should be considered a useful diagnostic tool in LRPAC or LAPAC before and after CRT.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902977","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":"Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis.","authors":"Yajing Gao, Kwei-Yan Liu, Wenfeng Xiao, Xueru Xie, Qiuyan Liang, Zikun Tu, Lan Yang, Hongmiao Yu, Haiyan Guo, Saihua Huang, Xiao Han, Jinrong Fu, Yufeng Zhou","doi":"10.7150/thno.95749","DOIUrl":"10.7150/thno.95749","url":null,"abstract":"<p><p><b>Rationale:</b> The aryl hydrocarbon receptor (AhR) functions in the regulation of intestinal inflammation, but knowledge of the underlying mechanisms in innate immune cells is limited. Here, we investigated the role of AhR in modulating the functions of macrophages in inflammatory bowel disease pathogenesis. <b>Methods:</b> The cellular composition of intestinal lamina propria CD45⁺ leukocytes in a dextran sulfate sodium (DSS)-induced mouse colitis model was determined by single-cell RNA sequencing. Macrophage pyroptosis was quantified by analysis of lactate dehydrogenase release, propidium iodide staining, enzyme-linked immunosorbent assay, western blot, and flow cytometry. Differentially expressed genes were confirmed by RNA-seq, RT-qPCR, luciferase assay, chromatin immunoprecipitation, and immunofluorescence staining. <b>Results:</b> AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45⁺ immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage. Mice with AhR deficiency in myeloid cells developed more severe dextran sulfate sodium induced colitis, with concomitant increased macrophage pyroptosis. Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells. Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 (<i>Odc1</i>) transcription, to enhance polyamine biosynthesis. The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K⁺ efflux. <i>AHR</i> expression was positively correlated with <i>ODC1</i> in intestinal mucosal biopsies from patients with ulcerative colitis. <b>Conclusions:</b> These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintaining intestinal homeostasis, providing potential targets for treatment of inflammatory bowel disease.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902978","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":"Methyl-CpG-binding 2 K271 lactylation-mediated M2 macrophage polarization inhibits atherosclerosis.","authors":"Liangqi Chen, Meiju Zhang, Xueyan Yang, Yanan Wang, Tuo Huang, Xin Li, Yunting Ban, Qifeng Li, Qingyuan Yang, Yongxiang Zhang, Yang Zheng, Di Wang, Xiaoqi Wang, Xiujie Shi, Maomao Zhang, Yong Sun, Jian Wu","doi":"10.7150/thno.94738","DOIUrl":"10.7150/thno.94738","url":null,"abstract":"<p><p><b>Rationale:</b> Posttranslational modifications of proteins have not been addressed in studies aimed at elucidating the cardioprotective effect of exercise in atherosclerotic cardiovascular disease (ASCVD). In this study, we reveal a novel mechanism by which exercise ameliorates atherosclerosis via lactylation. <b>Methods:</b> Using ApoE^-/- mice in an exercise model, proteomics analysis was used to identify exercise-induced specific lactylation of MeCP2 at lysine 271 (K271). Mutation of the MeCP2 K271 lactylation site in aortic plaque macrophages was achieved by recombinant adenoviral transfection. Explore the molecular mechanisms by which motility drives MeCP2 K271 lactylation to improve plaque stability using ATAC-Seq, CUT &Tag and molecular biology. Validation of the potential target RUNX1 for exercise therapy using Ro5-3335 pharmacological inhibition. <b>Results:</b> we showed that in ApoE^-/- mice, methyl-CpG-binding protein 2 (MeCP2) K271 lactylation was observed in aortic root plaque macrophages, promoting pro-repair M2 macrophage polarization, reducing the plaque area, shrinking necrotic cores, reducing plaque lipid deposition, and increasing collagen content. Adenoviral transfection, by introducing a mutant at lysine 271, overexpressed MeCP2 K271 lactylation, which enhanced exercise-induced M2 macrophage polarization and increased plaque stability. Mechanistically, the exercise-induced atheroprotective effect requires an interaction between MeCP2 K271 lactylation and H3K36me3, leading to increased chromatin accessibility and transcriptional repression of RUNX1. In addition, the pharmacological inhibition of the transcription factor RUNX1 exerts atheroprotective effects by promoting the polarization of plaque macrophages towards the pro-repair M2 phenotype. <b>Conclusions:</b> These findings reveal a novel mechanism by which exercise ameliorates atherosclerosis via MeCP2 K271 lactylation-H3K36me3/RUNX1. Interventions that enhance MeCP2 K271 lactylation have been shown to increase pro-repair M2 macrophage infiltration, thereby promoting plaque stabilization and reducing the risk of atherosclerotic cardiovascular disease. We also established RUNX1 as a potential drug target for exercise therapy, thereby providing guidance for the discovery of new targets.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902940","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}