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Overcoming the Blood-Brain Tumor Barrier with docetaxel-Loaded Mesoporous Silica Nanoparticles for Treatment of Temozolomide-Resistant Glioblastoma

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ACS Applied Materials and Interfaces 2024年第17期16卷 21722-21735页

作者： Hsu, Tsung-I Chen, Yi-Ping Zhang, Rong-Lin Chen, Zih-An Wu, Cheng-Hsun Chang, Wen-Chang Mou, Chung-Yuan Chan, Hardy Wai-Hong Wu, Si-Han Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University and National Health Research Institutes Taipei110 Taiwan International Master Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei110 Taiwan Graduate Institute of Nanomedicine and Medical Engineering Taipei Medical University Taipei110 Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei110 Taiwan Nano Targeting & Therapy Biopharma Inc. Taipei110 Taiwan Graduate Institute of Medical Sciences College of Medicine Taipei Medical University Taipei110 Taiwan Department of Chemistry National Taiwan University Taipei106 Taiwan

While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (dTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and dTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, dTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free dTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by dTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate dTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations. © 2024 The Authors. Published by American Chemical Society.

关键词： Tumors

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Saccades, attentional orienting and disengagement: The effects of anodal tdCS over right posterior parietal cortex (PPC) and frontal eye field (FEF)

Saccades, attentional orienting and disengagement: The effec...

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2021 ACM Symposium on Eye Tracking Research and Applications, ETRA 2021

作者： diana, Lorenzo Pilastro, Patrick E., N. Aiello A., K. Eberhard-Moscicka R., M. Müri N., Bolognini Ph.D. Program in Neuroscience Department of Medicine and Surgery University of Milano-Bicocca Italy Department of Psychology University of Milano-Bicocca Italy

ISBN: (纸本)9781450383455

In the present work, we applied anodal transcranial direct current stimulation (tdCS) over the posterior parietal cortex (PPC) and frontal eye field (FEF) of the right hemisphere in healthy subjects to modulate attentional orienting and disengagement in a gap-overlap task. Both stimulations led to bilateral improvements in saccadic reaction times (SRTs), with larger effects for gap trials. However, analyses showed that the gap effect was not affected by tdCS. Importantly, we observed significant effects of baseline performance that may mediate side- and task-specific effects of brain stimulation. © 2021 ACM.

关键词： Visuo-spatial attention Saccades Frontal Eye Field Posterior Parietal Cortex tdCS

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Atrophy of the cholinergic regions advances from early to late mild cognitive impairment

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Neuroradiology 2024年第4期66卷 543-556页

作者： Lai, Ying-Liang Larry Hsu, Fei-Ting Yeh, Shu-Yi Kuo, Yu-Tzu Lin, Hui-Hsien Lin, Yi-Chun Kuo, Li-Wei Chen, Cheng-Yu Liu, Hua-Shan Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University and National Health Research Institutes Taipei Taiwan Department of Biological Science and Technology China Medical University Taichung Taiwan School of Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei Taiwan CT/MR Division Rotary Trading CO. LTD Taipei Taiwan Institute of Biomedical Engineering and Nanomedicine National Health Research Institutes Miaoli Taiwan Institute of Medical Device and Imaging National Taiwan University College of Medicine Taipei Taiwan Department of Radiology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Medical Imaging Taipei Medical University Hospital Medical University Taipei Taiwan International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University Taipei Taiwan

Purpose: We investigated the volumetric changes in the components of the cholinergic pathway for patients with early mild cognitive impairment (EMCI) and those with late mild cognitive impairment (LMCI). The effect of patients’ apolipoprotein 4 (APOE-ε4) allele status on the structural changes were analyzed. Methods: Structural magnetic resonance imaging data were collected. Patients’ demographic information, plasma data, and validated global cognitive composite scores were included. Relevant features were extracted for constructing machine learning models to differentiate between EMCI (n = 312) and LMCI (n = 541) and predict patients’ neurocognitive function. The data were analyzed primarily through one-way analysis of variance and two-way analysis of covariance. Results: Considerable differences were observed in cholinergic structural changes between patients with EMCI and LMCI. Cholinergic atrophy was more prominent in the LMCI cohort than in the EMCI cohort (P < 0.05 family-wise error corrected). APOE-ε4 differentially affected cholinergic atrophy in the LMCI and EMCI cohorts. For LMCI cohort, APOE-ε4 carriers exhibited increased brain atrophy (left amygdala: P = 0.001;right amygdala: P = 0.006, and right Ch123, P = 0.032). EMCI and LCMI patients showed distinctive associations of gray matter volumes in cholinergic regions with executive (R² = 0.063 and 0.030 for EMCI and LMCI, respectively) and language (R² = 0.095 and 0.042 for EMCI and LMCI, respectively) function. Conclusions: Our data confirmed significant cholinergic atrophy differences between early and late stages of mild cognitive impairment. The impact of the APOE-ε4 allele on cholinergic atrophy varied between the LMCI and EMCI groups. © 2024, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

关键词： APOE-ε4 allele cholinergic pathway Early mild cognitive impairment (EMCI) mild cognitive impairment (MCI) nucleus basalis of Meynert

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Unveiling Multivariate EEG Features: A Novel Approach to Enhancing AdHd diagnosis Through Visual and Auditory Attention Tests

Unveiling Multivariate EEG Features: A Novel Approach to Enh...

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2023 International Conference on Fuzzy Theory and Its Applications, iFUZZY 2023

作者： Fan, Zuo-Cian Lin, Ro-Wei Tsai, Ching-Shu Chou, Wen-Jiun Li, Chia-Jung Huang, Zih-Jun Shih, Bin-Yu Wang, Liang-Jen Ko, Li-Wei Department of Biological Science & Technology Hsinchu300 Taiwan National Yang Ming Chiao Tung University International Ph.D. Program in Interdisciplinary Neuroscience Hsinchu300 Taiwan Kaohsiung Chang Gung Memorial Hospit Department of Child and Adolescent Psychiatry National Yang Ming Chiao Tung University Institute of Electrical and Control Engineering Department of Electronics and Electrical Engineering Hsinchu300 Taiwan

ISBN: (纸本)9798350305791

We sought to revolutionize the classification of Attention-deficit/Hyperactivity disorder (AdHd) by pioneering an innovative approach that seamlessly integrated auditory and visual tests with electroencephalogram (EEG) coherence analysis, forming the foundation for our Support Vector Machine (SVM) models. Our primary objective was to achieve precise differentiation between individuals with AdHd and those without, aiming to reshape the landscape of AdHd diagnosis and early intervention. We constructed an SVM model based on CATA coherence, incorporating a carefully selected set of 180 features, and another grounded in CPT coherence with 70 features. Astonishingly, our exploration uncovered that a model incorporating CATA's coherence and Power Spectral density (PSd) as features achieved an astounding accuracy rate of 97.7%, using only half the number of features. This revelation hints at untapped potential for multivariate advancements in the realm of AdHd classification. The landscape of AdHd diagnosis and intervention is perpetually evolving, most notably with the FdA's approval of game therapy for AdHd. Leveraging the transformative power of our findings, we envision the development of user-friendly game therapies for in-home use, empowering both clinicians and parents alike. This marks a paradigm shift in the realm of AdHd intervention, offering objective, data-driven tools for the early management of AdHd. Gamified therapy not only enhances accessibility but also fosters engagement and compliance, all of which are pivotal in the long-term care of individuals with AdHd. In summary, our study represents a significant advancement in our comprehension and classification of AdHd. By fusing auditory and visual tests with EEG coherence analysis, fortified by state-of-the-art machine learning techniques, we have achieved an unprecedented level of accuracy in identifying individuals with AdHd. Our findings, aligned with the FdA-approved game therapy, offer a glimpse into a

关键词： Electroencephalography

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Structure-guided Redesign of OxyR-based Optogenetic Reporters for Sensitive Monitoring of Intracellular H2O2 Real-time

Structure-guided Redesign of OxyR-based Optogenetic Reporter...

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Optics and the Brain, BRAIN 2023 - Part of Optica Biophotonics Congress: Optics in the Life Sciences 2023

作者： Lee, Justin daho Wang, Yihan Nguyen, Amanda Berndt, Andre Molecular Engineering Ph.D. Program University of Washington SeattleWA98195 United States Department of Bioengineering University of Washington SeattleWA98195 United States Institute for Stem Cell and Regenerative Medicine University of Washington SeattleWA98109 United States Department of Pharmacology Center for Neuroscience of Addiction Pain and Emotion University of Washington SeattleWA98195 United States

OxyR is a protein exhibiting exceptional sensitivity and specificity towards H2O2. However, OxyR-based optogenetic sensors do not closely recapitulate the native sensitivity and kinetics. Here, we discuss a novel desi... 详细信息

ISBN: (纸本)9781957171210

关键词： diffusion Molecules Proteins Sensor performance Sensors Strain

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Equilibrative nucleoside transporter 3 supports microglial functions and protects against the progression of Huntington's disease in the mouse model

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Brain, Behavior, and Immunity 2024年 120卷 413-429页

作者： Lu, Ying-Sui Hung, Wei-Chien Hsieh, Yu-Ting Tsai, Pei-Yuan Tsai, Tsai-Hsien Fan, Hsiu-Han Chang, Ya-Gin Cheng, Hui-Kuei Huang, Shen-Yan Lin, Hsin-Chuan Lee, Yan-Hua Shen, Tzu-Hsiang Hung, Bing-Yu Tsai, Jin-Wu dzhagalov, Ivan Cheng, Irene Han-Juo Lin, Chun-Jung Chern, Yijuang Hsu, Chia-Lin Institute of Microbiology and Immunology National Yang Ming Chiao Tung University Taipei Taiwan Taiwan International Graduate Program in Molecular Medicine National Yang Ming Chiao Tung University and Academia Sinica Taipei Taiwan Institute of Brain Science National Yang Ming Chiao Tung University Taipei Taiwan Institute of Biomedical Sciences Academia Sinica Taipei Taiwan Taiwan International Graduate Program in Interdisciplinary Neuroscience National Yang Ming Chiao Tung University and Academia Sinica Taipei Taiwan Biomedical Industry Ph.D. Program National Yang Ming Chiao Tung University Taipei Taiwan Brain Research Center National Yang Ming Chiao Tung University Taipei Taiwan School of Pharmacy College of Medicine National Taiwan University Taipei Taiwan

Huntington's disease (Hd) is a hereditary neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric symptoms. Currently, there is no cure, and only limited treatments are available to manage the symptoms and to slow down the disease's progression. The molecular and cellular mechanisms of Hd's pathogenesis are complex, involving immune cell activation, altered protein turnover, and disturbance in brain energy homeostasis. Microglia have been known to play a dual role in Hd, contributing to neurodegeneration through inflammation but also enacting neuroprotective effects by clearing mHTT aggregates. However, little is known about the contribution of microglial metabolism to Hd progression. This study explores the impact of a microglial metabolite transporter, equilibrative nucleoside transporter 3 (ENT3), in Hd. Known as a lysosomal membrane transporter protein, ENT3 is highly enriched in microglia, with its expression correlated with Hd severity. Using the R6/2 ENT3^−/− mouse model, we found that the deletion of ENT3 increases microglia numbers yet worsens Hd progression, leading to mHTT accumulation, cell death, and disturbed energy metabolism. These results suggest that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes. © 2024 The Authors

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Estimating the volume of penumbra in rodents using dTI and stack-based ensemble machine learning framework

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European Radiology Experimental 2024年第1期8卷 59页

作者： Kuo, duen-Pang Chen, Yung-Chieh Li, Yi-Tien Cheng, Sho-Jen Hsieh, Kevin Li-Chun Kuo, Po-Chih Ou, Chen-Yin Chen, Cheng-Yu Department of Medical Imaging Taipei Medical University Hospital No.250 Wu Hsing Street Taipei Taiwan Translational Imaging Research Center Taipei Medical University Hospital Taipei Taiwan Research Center for Neuroscience Taipei Medical University Taipei Taiwan Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei Taiwan Department of Computer Science National Tsing Hua University Hsinchu Taiwan Research Center for Artificial Intelligence in Medicine Taipei Medical University Taipei Taiwan Department of Radiology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan Department of Radiology National Defense Medical Center Taipei Taiwan

Background: This study investigates the potential of diffusion tensor imaging (dTI) in identifying penumbral volume (PV) compared to the standard gadolinium-required perfusion–diffusion mismatch (PdM), utilizing a stack-based ensemble machine learning (ML) approach with enhanced explainability. Methods: Sixteen male rats were subjected to middle cerebral artery occlusion. The penumbra was identified using PdM at 30 and 90 min after occlusion. We used 11 dTI-derived metrics and 14 distance-based features to train five voxel-wise ML models. The model predictions were integrated using stack-based ensemble techniques. ML-estimated and PdM-defined PVs were compared to evaluate model performance through volume similarity assessment, the Pearson correlation analysis, and Bland–Altman analysis. Feature importance was determined for explainability. Results: In the test rats, the ML-estimated median PV was 106.4 mL (interquartile range 44.6–157.3 mL), whereas the PdM-defined median PV was 102.0 mL (52.1–144.9 mL). These PVs had a volume similarity of 0.88 (0.79–0.96), a Pearson correlation coefficient of 0.93 (p < 0.001), and a Bland–Altman bias of 2.5 mL (2.4% of the mean PdM-defined PV), with 95% limits of agreement ranging from -44.9 to 49.9 mL. Among the features used for PV prediction, the mean diffusivity was the most important feature. Conclusions: Our study confirmed that PV can be estimated using dTI metrics with a stack-based ensemble ML approach, yielding results comparable to the volume defined by the standard PdM. The model explainability enhanced its clinical relevance. Human studies are warranted to validate our findings. Relevance statement: The proposed dTI-based ML model can estimate PV without the need for contrast agent administration, offering a valuable option for patients with kidney dysfunction. It also can serve as an alternative if perfusion map interpretation fails in the clinical setting. Key points: • Penumbral volume can be estimated by dTI combi

关键词： Animals diffusion tensor imaging Infarction (middle cerebral artery) Ischemic stroke Machine learning

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The regulation of emotions associated with social exclusion: modulating effects of tdCS on patients with borderline personality disorder

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Brain Stimulation 2023年第1期16卷 325-326页

作者： Gallucci, Alessia Lisco, Alessandro Fabietti, Chiara Preti, Emaluele Riva, Paolo de Panfilis, Chiara Romero Lauro, Leonor Josefina Ph.D. Program in Neuroscience School of Medicine and Surgery University of Milano-Bicocca Italy NeuroMi University of Milano-Bicocca Italy Department of Medicine and Surgery Unit of Neuroscience University of Parma Italy Department of Mental Health Local Health Agency Italy Department of Psychology University of Milan-Bicocca Italy Department of Mental Health Local Health Agency Parma Italy

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Inhibition of MMP8 effectively alleviates manic-like behavior and reduces neuroinflammation by modulating astrocytic CEBPd

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Journal of Neuroinflammation 2024年第1期21卷 1页

作者： Wang, Tzu-Yun Weng, Eddie Feng-Ju Hsu, Yun-Chen Shiu, Lu-Ping Huang, Teng-Wei Wu, Hsuan-Cheng Hong, Jau-Shyong Wang, Shao-Ming Department of Psychiatry National Cheng Kung University Hospital College of Medicine National Cheng Kung University Tainan Taiwan Neuroscience and Brain Disease Center China Medical University Taichung Taiwan Graduate Institute of Biomedical Sciences College of Medicine China Medical University Taichung 404333 Taiwan School of Medicine College of Medicine China Medical University Taichung Taiwan Ph.D. Program for Aging China Medical University Taichung Taiwan Neurobiology Laboratory National Institute of Environmental Health Sciences National Institutes of Health 111 T.W. Alexander Dr. Research Triangle Park Durham 27709 NC United States

There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na+/K+-ATPase, has been implicated in the mouse model with manic-like behavi... 详细信息

There is an intrinsic relationship between psychiatric disorders and neuroinflammation, including bipolar disorder. Ouabain, an inhibitor of Na⁺/K⁺-ATPase, has been implicated in the mouse model with manic-like behavior. However, the molecular mechanisms linking neuroinflammation and manic-like behavior require further investigation. CCAAT/Enhancer-Binding Protein delta (CEBPd) is an inflammatory transcription factor that contributes to neurological disease progression. In this study, we demonstrated that the expression of CEBPd in astrocytes was increased in ouabain-treated mice. Furthermore, we observed an increase in the expression and transcript levels of CEBPd in human primary astrocytes following ouabain treatment. Transcriptome analysis revealed high MMP8 expression in human primary astrocytes following CEBPd overexpression and ouabain treatment. We confirmed that MMP8 is a CEBPd-regulated gene that mediates ouabain-induced neuroinflammation. In our animal model, treatment of ouabain-injected mice with M8I (an inhibitor of MMP8) resulted in the inhibition of manic-like behavior compared to ouabain-injected mice that were not treated with M8I. Additionally, the reduction in the activation of astrocytes and microglia was observed, particularly in the hippocampal CA1 region. Excessive reactive oxygen species formation was observed in ouabain-injected mice, and treating these mice with M8I resulted in the reduction of oxidative stress, as indicated by nitrotyrosine staining. These findings suggest that MMP8 inhibitors may serve as therapeutic agents in mitigating manic symptoms in bipolar disorder. © The Author(s) 2024.

关键词： Bipolar disease CEBPd MMP8 Neuroinflammation Ouabain-induced manic-like behavior

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Amelioration of the brain structural connectivity is accompanied with changes of gut microbiota in a tuberous sclerosis complex mouse model

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Translational Psychiatry 2024年第1期14卷 68页

作者： Hsieh, Christine Chin-jung Lo, Yu-Chun Wang, Hsin-Hui Shen, Hsin-Ying Chen, You-Yin Lee, Yi-Chao Biomedical Translation Research Center Academia Sinica Taipei Taiwan Ph.D. Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei Taiwan Neuroscience Research Center Taipei Medical University Taipei Taiwan Department of Biomedical Engineering National Yang Ming Chiao Tung University Taipei Taiwan International Master Program in Medical Neuroscience College of Medical Science and Technology Taipei Medical University Taipei Taiwan

Tuberous sclerosis complex (TSC) is a genetic disease that causes benign tumors and dysfunctions in many organs, including the brain. Aside from the brain malformations, many individuals with TSC exhibit neuropsychiatric symptoms. Among these symptoms, autism spectrum disorder (ASd) is one of the most common co-morbidities, affecting up to 60% of the population. Past neuroimaging studies strongly suggested that the impairments in brain connectivity contribute to ASd, whether or not TSC-related. Specifically, the tract-based diffusion tensor imaging (dTI) analysis provides information on the fiber integrity and has been used to study the neuropathological changes in the white matter of TSC patients with ASd symptoms. In our previous study, curcumin, a diet-derived mTOR inhibitor has been shown to effectively mitigate learning and memory deficits and anxiety-like behavior in Tsc2 ^+/− mice via inhibiting astroglial proliferation. Recently, gut microbiota, which is greatly influenced by the diet, has been considered to play an important role in regulating several components of the central nervous system, including glial functions. In this study, we showed that the abnormal social behavior in the Tsc2 ^+/− mice can be ameliorated by the dietary curcumin treatment. Second, using tract-based dTI analysis, we found that the Tsc2 ^+/− mice exhibited altered fractional anisotropy, axial and radial diffusivities of axonal bundles connecting the prefrontal cortex, nucleus accumbens, hypothalamus, and amygdala, indicating a decreased brain network. Third, the dietary curcumin treatment improved the dTI metrics, in accordance with changes in the gut microbiota composition. At the bacterial phylum level, we showed that the abundances of Actinobacteria, Verrucomicrobia, and Tenericutes were significantly correlated with the dTI metrics FA, Ad, and Rd, respectively. Finally, we revealed that the expression of myelin-associated proteins, myelin bassic p

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