Theranostics最新文献

{"title":"Collagen-targeted PET imaging for progressive experimental lung fibrosis quantification and monitoring of efficacy of anti-fibrotic therapies.","authors":"Alexandre Magno Maneschy Dias, Olivier Burgy, Mathieu Moreau, Victor Goncalves, Lenny Pommerolle, Romain Douhard, Alan Courteau, Alex Helbling, Mélanie Guillemin, John Simonet, Alexandra Oudot, Carmen Garrido, Philippe Bonniaud, Françoise Goirand, Bertrand Collin, Pierre-Simon Bellaye","doi":"10.7150/thno.106367","DOIUrl":"10.7150/thno.106367","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by an excessive collagen deposition ultimately leading to tissue stiffening and functional decline. Beyond IPF, other progressive pulmonary fibrosis are often associated with connective tissue diseases and may develop in ∼18-32% of patients. Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression without curing it. The current lack of biomarker to accurately assess and predict disease progression and therapy efficacy for IPF remains a major clinical concern. <b>Methods:</b> In our study, collagen deposition was monitored in bleomycin-induced lung fibrosis in mice by <i>in vivo</i> molecular imaging using a collagen-targeted radiopharmaceutical, [⁶⁸Ga]Ga-NODAGA-collagelin. Fibrosis progression was also monitored using computed tomography, the gold standard technique to detect lung fibrosis in patients. <b>Results:</b> We demonstrated that the bleomycin-induced increase in collagen lung content can be accurately quantified by [⁶⁸Ga]Ga-NODAGA-collagelin PET imaging in correlation with disease stage and severity. The lung uptake of [⁶⁸Ga]Ga-NODAGA-collagelin was mainly found in fibrotic areas of lungs in bleomycin-receiving mice. Most interestingly, [⁶⁸Ga]Ga-NODAGA-collagelin PET imaging allowed the <i>in vivo</i> non-invasive monitoring of nintedanib efficacy as well as the anti-fibrotic effect of the JAK inhibitor, tofacitinib. <b>Conclusion:</b> Thus, collagen-targeted PET imaging appears as a promising non-invasive tool for staging, monitoring and prediction of disease progression and therapy efficacy towards personalized medicine in IPF.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2092-2103"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483634","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":"Neural mechanism of trigeminal nerve stimulation recovering defensive arousal responses in traumatic brain injury.","authors":"Qian Zhang, Haiyun Ma, Lifang Huo, Shaoling Wang, Qian Yang, Zhimin Ye, Jie Cao, Shaoling Wu, Chao Ma, Congping Shang","doi":"10.7150/thno.106323","DOIUrl":"10.7150/thno.106323","url":null,"abstract":"<p><p>The arousal state is defined as the degree to which an individual is aware of themselves and their surroundings, and is a crucial component of consciousness. Trigeminal nerve stimulation (TNS), a non-invasive clinical neuromodulation technique, has shown potential in aiding the functional recovery of patients with impaired consciousness. Understanding the specific neuronal subpopulations and circuits through which TNS improves arousal states is essential for advancing its clinical application. <b>Methods:</b> A mouse model of traumatic brain injury (TBI) was established using a weight-drop technique to induce neurological dysfunction, and the arousal state was assessed through visual and auditory defensive responses. Techniques such as viral tracing, chemogenetics, patch-clamp recordings, calcium signaling, and neurotransmitter probes were employed to investigate the relevant subpopulations of trigeminal ganglion (TG) neurons and the underlying mechanisms in the central nervous system. <b>Results:</b> Neuronal subgroups involved in TNS therapy at the key peripheral nucleus, the TG, were identified. Two distinct types of neurons were found to contribute differently: The Tac1+TG-locus coeruleus (LC)-superior colliculus (SC) pathway elevated noradrenaline levels in the SC, enhancing receptive field sensitivity recovery in TBI mice; the Piezo2+TG-paraventricular hypothalamic nucleus (PVN)-substantia nigra pars compacta (SNc)-dorsal striatum (DS) pathway initiated dopamine (DA) release in the DS, ameliorating motor disorders in TBI mice. <b>Conclusion:</b> These pathways contribute to the improvement of defensive arousal responses from different perspectives. The findings from this study imply that TNS effectively restores defensive arousal responses to visual and auditory threats in mice suffering from TBI, offering insights that may facilitate the implementation of TNS therapy in clinical settings.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2315-2337"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483841","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":"Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies.","authors":"Hong Wang, Fei Zhou, Wenqing Qin, Yun Yang, Xiaojiaoyang Li, Runping Liu","doi":"10.7150/thno.105276","DOIUrl":"10.7150/thno.105276","url":null,"abstract":"<p><p>Cancer remains a major challenge to global public health, with rising incidence and high mortality rates. The tumor microenvironment (TME) is a complex system of immune cells, fibroblasts, extracellular matrix (ECM), and blood vessels that form a space conducive to cancer cell proliferation. Myeloid-derived suppressor cells (MDSCs) are abundant in tumors, and they drive immunosuppression through metabolic reprogramming in the TME. This review describes how metabolic pathways such as glucose metabolism, lipid metabolism, amino acid metabolism, and adenosine metabolism have a significant impact on the function of MDSCs by regulating their immunosuppressive activity and promoting their survival and expansion in tumors. The review also explores key metabolic targets in MDSCs and strategies to modulate MDSC metabolism to improve the tumor immune microenvironment and enhance anti-tumor immune responses. Understanding these pathways can provide insight into potential therapeutic targets for modulating MDSC activity and improving outcomes of cancer immunotherapies.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2159-2184"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483932","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":"Histone lactylation-driven B7-H3 expression promotes tumor immune evasion.","authors":"Zhibo Ma, Jincui Yang, Wenlong Jia, Le Li, Yixin Li, Junjie Hu, Wei Luo, Ronghui Li, Dawei Ye, Peixiang Lan","doi":"10.7150/thno.105947","DOIUrl":"10.7150/thno.105947","url":null,"abstract":"<p><p><b>Rationale:</b> Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous immune checkpoints, particularly those within the B7 family. Elucidating the mechanisms that govern the induction of B7 family molecules is crucial for the advancement of immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, is suggested may play a role in reshaping the tumor microenvironment and facilitating immune evasion. <b>Methods:</b> We analyzed the glycolysis pathway's enrichment in patients with immune-evading tumors and assessed the impact of lactate treatment on the antitumor immunity of CD8⁺ T cells in the tumor microenvironment. We interrupted glycolysis using lactate dehydrogenase A (<i>LDHA</i>) knockdown and sodium oxamate, and evaluated its effects on CD8⁺ T cell cytotoxicity. Additionally, we investigated the correlation between B7-H3 expression and the glycolysis pathway, and explored the molecular mechanisms underlying lactate-induced B7-H3 expression. <b>Results:</b> Our findings revealed that the glycolysis pathway was highly enriched in immune-evading tumors. Lactate treatment inhibited the antitumor immunity of CD8⁺ T cells, whereas interruption of glycolysis via LDHA knockdown or treatment with sodium oxamate augmented the cytotoxicity of CD8⁺ T cells, effectively counteracting tumor immune evasion. B7-H3 expression was found to be closely linked with the glycolysis pathway. Mechanistically, lactate-upregulated H3K18la directly bound to the B7-H3 promoter in conjunction with the transcription factor Creb1 and its co-activator Ep300, leading to increased B7-H3 expression and contributing to tumor progression by compromising the proportion and cytotoxicity of tumor-infiltrating CD8⁺ T cells. In mouse tumor bearing models, inhibiting glycolysis and B7-H3 expression suppressed tumor cell growth, activated tumor-infiltrating CD8⁺ T cells, and demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced the efficacy of anti-PD-1 treatment. <b>Conclusions:</b> This study uncovers a novel mechanism by which lactate modulates the immune microenvironment through the glycolysis pathway and B7-H3 expression, providing new avenues for lactate metabolism-targeted tumor immunotherapy.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2338-2359"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483857","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":"Autophagy-enhanced nanosonosensitizer mediated sonodynamic therapy for post-myocardial infarction neuromodulation and arrhythmia prevention.","authors":"Haoyuan Hu, Songyun Wang, Qian Li, Jiahui Zhao, Yida Pang, Jiale Wang, Huijun Wu, Xinqi Wang, Ye Cheng, Mengran Yu, Xinyue Yin, Yan Zhang, Lilei Yu, Yao Sun, Hong Jiang","doi":"10.7150/thno.103780","DOIUrl":"10.7150/thno.103780","url":null,"abstract":"<p><p><b>Rationale:</b> Sympathetic hyperactivation and neuroinflammation are the main triggers of malignant ventricular arrhythmias (VAs) after myocardial infarction (MI). Previous studies proved that photothermal therapy (PTT) and photodynamic therapy (PDT) could reduce MI-induced VAs by inhibiting neuroinflammation. However, the limited penetration depth and potential phototoxicity of phototherapy impose constraints on its further application. As a treatment strategy derived from phototherapy, sonodynamic therapy (SDT) offers exceptional advantages, including excellent penetration capability, temporal-spatial controllability, superior efficacy and minimal side effects. Therefore, it is worthwhile to investigate the effects of sonodynamic modulation on neuroinflammation and arrhythmia prevention. <b>Methods:</b> We designed a long-wavelength emissive sonosensitizer (named <b>BBTD-TPA</b>) based on donor-acceptor-donor scaffold. Subsequently, the compound was encapsulated in DSPE-PEG5000 to form <b>BBTD-TPA</b> nanoparticles (NPs). <i>In vitro</i> experiments were conducted to determine the optimal concentration of <b>BBTD-TPA</b> NPs-mediated SDT and to verify the effects and pathways on autophagy in BV2 cells. The distribution and metabolism of <b>BBTD-TPA</b> NPs <i>in vivo</i> were assessed by NIR-II fluorescence imaging. Finally, <i>in vivo</i> studies were performed to assess the effect of <b>BBTD-TPA</b> NPs-mediated SDT on post-MI sympathetic neuroinflammation and the occurrence of VAs. <b>Results:</b> <i>In vitro</i> studies demonstrated that <b>BBTD-TPA</b> NPs combined with LIFU could promote microglial autophagy via the ROS-AMPK-mTOR pathway. <b>BBTD-TPA</b> NPs were further microinjected into the paraventricular nucleus (PVN), real-time NIR-II fluorescence imaging showed that <b>BBTD-TPA</b> NPs could remain in the PVN for up to 12 h and be metabolized through the liver and kidney. Further <i>in vivo</i> results verified that <b>BBTD-TPA</b> NPs-mediated SDT could inhibit sympathetic nervous activity, and inflammatory responses, thus preventing MI-induced VAs. <b>Conclusion: BBTD-TPA</b> NPs-mediated SDT can promote microglial autophagy and inhibit sympathetic neuroinflammation, thus reducing MI-induced VAs. The current research may inspire a novel strategy for neuromodulation and arrhythmia prevention, providing broader prospects for clinical translation of nanomedical technology.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2201-2214"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483582","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":"Microalgae-based bacteria for oral treatment of ASD through enhanced intestinal colonization and homeostasis.","authors":"Rongrong Yang, Li Ma, Huan Peng, Yifang Zhai, Gengyao Zhou, Linjuan Zhang, Lixia Zhuo, Wei Wu, Yuxi Guo, Jiao Han, Linlin Jing, Xinyu Zhou, Xiancang Ma, Yan Li","doi":"10.7150/thno.103737","DOIUrl":"10.7150/thno.103737","url":null,"abstract":"<p><p><b>Rationale:</b> Exogenous supplementation of beneficial intestinal bacteria can alleviate the behavioural symptoms of psychiatric disorders, such as autism spectrum disorder (ASD), through gut-brain interactions. However, the application of beneficial bacteria, such as <i>Lactobacillus reuteri</i> (<i>L. reuteri</i>), for treating ASD is hindered by limited gut colonization. <b>Methods:</b> Utilizing <i>Spirulina platensis</i> (SP) as a natural microcarrier for intestinal bacteria, a safer and more natural binding approach was employed to bind intestinal bacteria to the surface of SP to produce SP-intestinal bacteria. Due to the high adhesion efficiency and long residence time of SP in the intestines, SP-intestinal bacteria exhibit stronger intestinal colonization ability and better therapeutic effects on ASD. <b>Results:</b> SP is an effective carrier that can bind and deliver bacteria of different shapes and with different gram-staining properties. SP-intestinal bacteria exhibited enhanced colonization capabilities both <i>ex vivo</i> and <i>in vivo</i>. Further research showed that SP-<i>L. reuteri</i> had greater intestinal colonization efficiency than <i>L. reuteri</i>. SP-<i>L. reuteri</i> showed a stronger therapeutic effect on alleviating social deficits in an ASD mouse model by modulating the gut microbiota, enhancing intestinal barrier integrity, reducing lipopolysaccharide entry into the blood and mediating the neuroinflammatory response in the paraventricular thalamic nucleus. <b>Conclusions:</b> This study reports a microalgae-assisted intestinal bacterial delivery system for enhancing intestinal bacterial transplantation for gut-brain axis- or other intestinal-related diseases.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2139-2158"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483934","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":"Neurotrophic factor-α1/carboxypeptidase E controls progression and reversal of Alzheimer's disease pathogenesis in mice.","authors":"Fang-Cheng Fan, Li-Ming Liu, Mei Guo, Yang Du, Yue-Wen Chen, Y Peng Loh, Yong Cheng","doi":"10.7150/thno.99908","DOIUrl":"10.7150/thno.99908","url":null,"abstract":"<p><p><b>Background:</b> Neurotrophic Factor-α1/Carboxypeptidase E (NF-α1/CPE) is a pivotal neuroprotective protein implicated in rescuing cognitive decline associated with Alzheimer's disease (AD). However, its direct role in AD pathogenesis remains unexplored. <b>Methods:</b> We utilized the Cre/LoxP system to diminish NF-α1/CPE expression, and employed AAV-mediated overexpression of NF-α1/CPE. <b>Results:</b> NF-α1/CPE expression was significantly down-regulated in advanced stages of AD and with age in 5xFAD mice. Reduced NF-α1/CPE levels in the hippocampus of 5xFAD mice increased plaque burden, microglial cell count, disrupted synaptogenesis, and intensified cognitive impairments at 5 and 7 months. However, by 9 months, no further progression of detrimental effects was observed. Overexpression of NF-α1/CPE markedly decreased amyloid plaque accumulation, mitigated spatial memory deficits, and normalized hippocampal synaptogenesis and microglial anomalies across early and late stages of the disease. <b>Conclusion:</b> NF-α1/CPE is a critical regulator of AD pathogenesis, offering promising therapeutic potential for reducing amyloid beta deposition and toxicity in AD.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2279-2292"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483847","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":"OTUD7B is a new deubiquitinase targeting p53.","authors":"Caoyuan Ding, Leixi Cao, Ruijie Wang, Qichen Wu, Mengfan Li, Jinjing Zhang, Rick F Thorne, Jinming Li, Jianli Ma, Mian Wu, Shundong Cang","doi":"10.7150/thno.103012","DOIUrl":"10.7150/thno.103012","url":null,"abstract":"<p><p><b>Rationale:</b> The tumor suppressor p53 safeguards against cellular transformation, with its expression regulated by diverse post-translational modifications (PTMs). While polyubiquitination by Mdm2 principally drives its proteasomal degradation, the identity of p53 deubiquitinases (DUBs) remains less well defined. This study investigates the role of the deubiquitinase enzyme OTUD7B in hepatocellular carcinoma (HCC), where it is notably downregulated and proposed to function as a tumor suppressor. <b>Methods:</b> Mass spectrometry screening of immunoprecipitates from HCC cells was used to identify OTUD7B-binding proteins. Co-immunoprecipitation assays with endogenous, ectopic, and mutant forms of OTUD7B and p53 assessed binding interactions and p53 polyubiquitination levels, respectively. Regulatory mechanisms were explored via luciferase reporter and chromatin immunoprecipitation (ChIP) assays. OTUD7B function was evaluated in vitro and in xenograft models using shRNA knockdown, overexpression, and CRISPR-Cas9 knockout. OTUD7B expression in normal and HCC tissues was analyzed by immunohistochemistry and immunoblotting. <b>Results:</b> We identified p53 as a binding partner of OTUD7B, confirming interactions with both wild-type and mutant p53 in HCC cells. OTUD7B was shown to remove lysine-linked polyubiquitin chains in p53, including those mediated by Mdm2, thereby stabilizing p53 by inhibiting its proteasomal degradation. Overexpression of OTUD7B suppressed growth in HCC cultures and xenografts through p53-dependent mitochondrial apoptosis, marked by PUMA and BAX induction. Conversely, OTUD7B knockdown promoted tumor growth. These effects were absent in p53-null or CRISPR-knockout cells, underscoring p53 as a key OTUD7B substrate. Additionally, OTUD7B expression was found to be transcriptionally repressed via p53-dependent mechanisms. Bioinformatics and <i>ex vivo</i> analysis revealed a positive correlation between OTUD7B and p53 protein levels in HCC tissues. <b>Conclusion:</b> OTUD7B plays a critical role in stabilizing both wild-type and mutant p53 in HCC cells, with its expression regulated through a mutual feedback loop involving p53. By inhibiting cell growth, OTUD7B exhibits tumor-suppressive properties, underscored by its atypical downregulation in patient tissues and its positive correlation with p53 expression. These findings highlight the clinical significance of OTUD7B and position it as a promising therapeutic target for modulating the p53 pathway in HCC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2121-2138"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143484013","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":"Epigenetic regulation-mediated disorders in dopamine transporter endocytosis: A novel mechanism for the pathogenesis of Parkinson's disease.","authors":"Ziqi Liang, Wanqing Liu, Mian Cao, Jiajun Cui, Jinshuai Lan, Yue Ding, Tong Zhang, Zizhao Yang","doi":"10.7150/thno.107436","DOIUrl":"10.7150/thno.107436","url":null,"abstract":"<p><p>Mechanisms such as DNA methylation, histone modifications, and non-coding RNA regulation may impact the endocytosis of dopamine transporter (DAT) by influencing processes like neuronal survival, thereby contributing to the initiation and progression of Parkinson's Disease (PD). Some small molecule inhibitors or natural bioactive compounds have the potential to modulate epigenetic processes, thereby reversing induced pluripotent stem cells (iPSCs) reprogramming and abnormal differentiation, offering potential therapeutic effects for PD. Although no specific DNA modification enzyme directly regulates DAT endocytosis, enzymes such as DNA methyltransferases (DNMTs) may indirectly influence DAT endocytosis by regulating the expression of genes associated with this process. DNA modifications impact DAT endocytosis by modulating key signaling pathways, including the (protein kinase C) PKC and D2 receptor (D2R) pathways. Key enzymes involved in RNA modifications that influence DAT endocytosis include m⁶A methyltransferases and other related enzymes. This regulation impacts the synthesis and function of proteins involved in DAT endocytosis, thereby indirectly affecting the process itself. RNA modifications regulate DAT endocytosis through various indirect pathways, as well as histone modifications. Key enzymes influence the expression of genes associated with DAT endocytosis by modulating the chromatin's accessibility and compaction state. These enzymes control the expression of proteins involved in regulating endocytosis, promoting endosome formation, and facilitating recycling processes. Through the modulation exerted by these enzymes, the speed of DAT endocytosis and recycling patterns are indirectly regulated, establishing a crucial epigenetic control point for the regulation of neurotransmitter transport. Based on this understanding, we anticipate that targeting these processes could lead to favorable therapeutic effects for early PD pathogenesis.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2250-2278"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483620","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":"OASL promotes immune evasion in pancreatic ductal adenocarcinoma by enhancing autolysosome-mediated degradation of MHC-I.","authors":"Xin Xing, Xia-Qing Li, Shi-Qi Yin, Hong-Tai Ma, Shu-Yu Xiao, Aziguli Tulamaiti, Yan Yang, Shu-Heng Jiang, Li-Peng Hu, Zhi-Gang Zhang, Yan-Miao Huo, Dong-Xue Li, Xiao-Mei Yang, Xue-Li Zhang","doi":"10.7150/thno.103494","DOIUrl":"10.7150/thno.103494","url":null,"abstract":"<p><p><b>Rationale:</b> Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a global prevalence and poor prognosis, largely due to immune escape mechanisms. However, the potential reasons for the decreased infiltration of cytotoxic T lymphocytes (CTLs) in PDAC remain inadequately understood. In this study, we aimed to elucidate the molecular mechanisms contributing to the low-CTLs infiltration in patients with PDAC. <b>Methods:</b> Bioinformatic analyses were used to identify key factors associated with low-CTLs infiltration in PDAC and the role of oligoadenylate synthetase-like (OASL) was mainly focused in our study. Immunohistochemistry (IHC) was used to assess the relationship between the expression of OASL and the prognosis of patients. Western blotting, Flow cytometry, Co-immunoprecipitation and Immunofluorescence were applied to elucidate the molecular mechanism by which OASL mediates immune escape in PDAC. The orthotopic PDAC models were constructed to evaluate the effects of <i>OASL</i>-knockdown on CD8⁺ T cells infiltration and tumor growth <i>in vivo.</i> <b>Results:</b> OASL was found to be significantly upregulated in PDAC and negatively correlated with the major histocompatibility complex class I (MHC-I) expression, which is associated with worse patient prognosis. Notably, <i>OASL-</i>knockdown leads to a significant increase in CD8⁺ T cell infiltration and slows tumor growth <i>in vivo</i>. Mechanistic studies revealed that <i>OASL</i> -knockdown restored the total and surface MHC-I level through impairing neighbor of BRCA1 gene 1 (NBR1)-mediated autophagy-lysosomal degradation of MHC-I. <b>Conclusions:</b> Targeting OASL enhances the immune response in PDAC, providing a novel therapeutic strategy to improve outcomes in PDAC patients.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 6","pages":"2104-2120"},"PeriodicalIF":12.4,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11840728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483926","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}